CA2283322C - Starter kit containing nicotinic acid compositions - Google Patents
Starter kit containing nicotinic acid compositions Download PDFInfo
- Publication number
- CA2283322C CA2283322C CA002283322A CA2283322A CA2283322C CA 2283322 C CA2283322 C CA 2283322C CA 002283322 A CA002283322 A CA 002283322A CA 2283322 A CA2283322 A CA 2283322A CA 2283322 C CA2283322 C CA 2283322C
- Authority
- CA
- Canada
- Prior art keywords
- nicotinic acid
- sustained release
- tablets
- night
- evening
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Abstract
The present invention further discloses a starter kit containing nicotinic acid in a sustained release formulation for titrating patients with hyperlipidemia.
Description
STARTER KIT CONTAINING NICOTINIC ACID COMPOSITION
FIELD OF THE INVENTION
This invention relates to a starter kit for titrating a patient diagnosed with hyperlipidemia with sustained release nicotinic acid compositions; the invention also relates to sustained release nicotinic acid tablets for use to titrate a patient diagnosed with hyperlipidemia; the invention further relates to the use of sustained release nicotinic acid tablets in the manufacture of a medicament to titrate a patient diagnosed with hyperlipidemia; still further the invention relates to a pharmaceutical formulation comprising a plurality of sustained release nicotinic acid tablets to titrate a patient diagnosed with hyperlipidemia.
This invention more generally relates to compositions of nicotinic acid useful for treating hyperlipidemia and methods of treating hyperlipidemia employing such compositions. In particular embodiments, the present invention employs a composition of nicotinic acid, derivatives and mixtures thereof, and a swelling agent to form a time release sustaining composition for nocturnal or evening dosing. Specifically, the present invention employs a composition of nicotinic acid and hydroxypropyl methylcellulose to treat hyperlipidemia in a once per day oral dosage form given during the evening hours.
BACKGROUND
Nicotinic acid has been used for many years in the treatment of hyperlipidemia. This compound has long been known to exhibit the beneficial effects of reducing total cholesterol, low density lipoproteins or "LDL cholesterol", triglycerides and apolipoprotein a (Lp(a)) in the human body, while increasing desirable high density lipoproteins or "HDL
cholesterol".
Nicotinic acid has normally been administered three times per day after meals.
This dosing regimen is known to provide a very beneficial effect on blood lipids as discussed in Knopp DOCSMTL: 1934481\1
FIELD OF THE INVENTION
This invention relates to a starter kit for titrating a patient diagnosed with hyperlipidemia with sustained release nicotinic acid compositions; the invention also relates to sustained release nicotinic acid tablets for use to titrate a patient diagnosed with hyperlipidemia; the invention further relates to the use of sustained release nicotinic acid tablets in the manufacture of a medicament to titrate a patient diagnosed with hyperlipidemia; still further the invention relates to a pharmaceutical formulation comprising a plurality of sustained release nicotinic acid tablets to titrate a patient diagnosed with hyperlipidemia.
This invention more generally relates to compositions of nicotinic acid useful for treating hyperlipidemia and methods of treating hyperlipidemia employing such compositions. In particular embodiments, the present invention employs a composition of nicotinic acid, derivatives and mixtures thereof, and a swelling agent to form a time release sustaining composition for nocturnal or evening dosing. Specifically, the present invention employs a composition of nicotinic acid and hydroxypropyl methylcellulose to treat hyperlipidemia in a once per day oral dosage form given during the evening hours.
BACKGROUND
Nicotinic acid has been used for many years in the treatment of hyperlipidemia. This compound has long been known to exhibit the beneficial effects of reducing total cholesterol, low density lipoproteins or "LDL cholesterol", triglycerides and apolipoprotein a (Lp(a)) in the human body, while increasing desirable high density lipoproteins or "HDL
cholesterol".
Nicotinic acid has normally been administered three times per day after meals.
This dosing regimen is known to provide a very beneficial effect on blood lipids as discussed in Knopp DOCSMTL: 1934481\1
-2-et al; "Contrasting Effects of Unmodified and Time-Release Forms of Niacin on Lipoproteins in Hyperlipidernic Subjects: Clues to Mechanism of Action of Niacin";
Metabolism 34/7, 1985, page 647. The chief advantage of this profile is the ability of nicotinic acid to decrease total cholesterol, LDL cholesterol, triglycerides and Lp(a) while increasing HDL particles. While such a regimen does produce beneficial effects, cutaneous flushing and the like still often occurs in the hyperlipidemics to whom the compound is administered.
In order to avoid or reduce the cutaneous flushing, a number of materials have been suggested for administration with an effective antihyperlipidemic amount of nicotinic acid, including guar gum in U.S. Pat. No. 4,965,252, and mineral salts as disclosed in U.S. Pat.
No. 5,023,245; or inorganic magnesium salts as reported in U.S. Pat. No.
4,911,917. These materials have been reported to avoid or reduce the cutaneous flushing side effect commonly associated with nicotinic acid treatment.
Another method of avoiding or reducing the side effects associated with immediate release niacin is the use of sustained release formulations. Sustained release formulations are designed to slowly release the compound from the tablet or capsule. The slow drug release reduces and prolongs blood levels of drug and thus minimizes the side effects.
Sustained release formulations of niacin have been developed, such as Nicobid.TM.
capsules (Rhone-Poulenc Rorer), Endur-acinTm (Innovite Corporation) and U.S. Pat. No.
5,126,145 which describes a sustained release niacin formulation containing two different types of hydroxypropyl methylcellulose and a hydrophobic component.
Studies in hyperlipidemic patients have been conducted with a number of sustained release niacin products. These studies have demonstrated that the sustained release products do not have the same advantageous lipid altering effects as immediate release niacin, and in fact often have a worse side effect profile compared to the immediate release product. The DOCSMTL: 1934481\1
Metabolism 34/7, 1985, page 647. The chief advantage of this profile is the ability of nicotinic acid to decrease total cholesterol, LDL cholesterol, triglycerides and Lp(a) while increasing HDL particles. While such a regimen does produce beneficial effects, cutaneous flushing and the like still often occurs in the hyperlipidemics to whom the compound is administered.
In order to avoid or reduce the cutaneous flushing, a number of materials have been suggested for administration with an effective antihyperlipidemic amount of nicotinic acid, including guar gum in U.S. Pat. No. 4,965,252, and mineral salts as disclosed in U.S. Pat.
No. 5,023,245; or inorganic magnesium salts as reported in U.S. Pat. No.
4,911,917. These materials have been reported to avoid or reduce the cutaneous flushing side effect commonly associated with nicotinic acid treatment.
Another method of avoiding or reducing the side effects associated with immediate release niacin is the use of sustained release formulations. Sustained release formulations are designed to slowly release the compound from the tablet or capsule. The slow drug release reduces and prolongs blood levels of drug and thus minimizes the side effects.
Sustained release formulations of niacin have been developed, such as Nicobid.TM.
capsules (Rhone-Poulenc Rorer), Endur-acinTm (Innovite Corporation) and U.S. Pat. No.
5,126,145 which describes a sustained release niacin formulation containing two different types of hydroxypropyl methylcellulose and a hydrophobic component.
Studies in hyperlipidemic patients have been conducted with a number of sustained release niacin products. These studies have demonstrated that the sustained release products do not have the same advantageous lipid altering effects as immediate release niacin, and in fact often have a worse side effect profile compared to the immediate release product. The DOCSMTL: 1934481\1
-3-major disadvantage of the sustained release formulations, as can be seen in Knopp et al., 1985, is the significantly lower reduction in triglycerides (-2% for the sustained release versus -38% for the immediate release) and lower increase in HDL cholesterol, represented as HDL2 particles which are known by the art to be most beneficial, (-5% for the sustained release versus +37% for the immediate release).
Additionally, sustained release niacin formulations have been noted as causing greater incidences of liver toxicity as described in Henken et al (Am J Med 91:1991 1991) and Dalton et al (Am J Med 93: 102 1992). There is also great concern regarding the potential of these formulations in disrupting glucose metabolism and uric acid levels.
In a recent edition of the JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
(JAMA), an article appeared which presented research results investigating the liver toxicity problems associated with a sustained release form of nicotinic acid.
"A Comparison of the Efficacy and Toxic Effects of Sustained- vs. Immediate-Release Niacin in Hypercholesterolemic Patients", McKenney et al., JAMA, Vol. 271, No. 9, Mar.
2, 1994, page 672. The article presented a study of twenty-three patients. Of that number, 12 or 52 percent were forced to withdraw because liver function tests (LFTs) increased indicating potential liver damage. The conclusion of the authors of that article was that the sustained release form of niacin "should be restricted from use."
A similar conclusion was reached in an article authored by representatives of the Food and Drug Administration and entitled "Hepatic Toxicity of Umnodified and Time-Release Preparations of Niacin", Rader, et al., THE AMERICAN JOURNAL OF MEDICINE, Vol.
92, January 1992, page 77. Because of these studies and similar conclusions drawn by other health care professionals, the sustained release forms of niacin have experienced limited utilization.
-3a-Therefore, it can be seen from the scientific literature that there is a need for development of a sustained release niacin formulation and a method of delivering said formulation which would provide hyperlipidemic patients with "balanced lipid alteration", i.e. reductions in total cholesterol, LDL cholesterol, triglycerides and Lp(a) as well as increases in HDL particles, with an acceptable safety profile, especially as regards liver toxicity and effects on glucose metabolism and uric acid levels.
SUMMARY OF THE INVENTION
In accordance with one aspect of the invention there is provided a starter kit for titrating a patient diagnosed with hyperlipidemia with sustained release nicotinic acid compositions comprising: (a) 7 375 mg nicotinic acid sustained release tablets; (b) 7 500 mg nicotinic acid sustained release tablets; (c) 7 750 mg nicotinic acid sustained release tablets; and a housing for containing said tablets.
In accordance with another aspect of the invention there is provided a combination of sustained release nicotinic acid tablets for use to titrate a patient diagnosed with hyperlipidemia, wherein said tablets each provide a single dose for administration only once a day during the evening or at night as follows:375 mg of nicotinic acid in a sustained release formulation each day for 7 days, 500 mg nicotinic acid in a sustained release formulation each day for 7 days, and 750 mg nicotinic acid in a sustained release formulation each day for 7 days.
In accordance with yet another aspect of the invention there is provided the use of sustained release nicotinic acid tablets in the manufacture of a medicament to titrate a patient diagnosed with hyperlipidemia, the medicament providing the tablets so as to provide a single dose for administration only once a day during the evening or at night as follows: 375 mg of nicotinic acid in a sustained release formulation each day for 7 days, 500 mg nicotinic acid in a sustained release formulation each day for 7 days, and 750 mg nicotinic acid in a sustained release formulation each day for 7 days.
Additionally, sustained release niacin formulations have been noted as causing greater incidences of liver toxicity as described in Henken et al (Am J Med 91:1991 1991) and Dalton et al (Am J Med 93: 102 1992). There is also great concern regarding the potential of these formulations in disrupting glucose metabolism and uric acid levels.
In a recent edition of the JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
(JAMA), an article appeared which presented research results investigating the liver toxicity problems associated with a sustained release form of nicotinic acid.
"A Comparison of the Efficacy and Toxic Effects of Sustained- vs. Immediate-Release Niacin in Hypercholesterolemic Patients", McKenney et al., JAMA, Vol. 271, No. 9, Mar.
2, 1994, page 672. The article presented a study of twenty-three patients. Of that number, 12 or 52 percent were forced to withdraw because liver function tests (LFTs) increased indicating potential liver damage. The conclusion of the authors of that article was that the sustained release form of niacin "should be restricted from use."
A similar conclusion was reached in an article authored by representatives of the Food and Drug Administration and entitled "Hepatic Toxicity of Umnodified and Time-Release Preparations of Niacin", Rader, et al., THE AMERICAN JOURNAL OF MEDICINE, Vol.
92, January 1992, page 77. Because of these studies and similar conclusions drawn by other health care professionals, the sustained release forms of niacin have experienced limited utilization.
-3a-Therefore, it can be seen from the scientific literature that there is a need for development of a sustained release niacin formulation and a method of delivering said formulation which would provide hyperlipidemic patients with "balanced lipid alteration", i.e. reductions in total cholesterol, LDL cholesterol, triglycerides and Lp(a) as well as increases in HDL particles, with an acceptable safety profile, especially as regards liver toxicity and effects on glucose metabolism and uric acid levels.
SUMMARY OF THE INVENTION
In accordance with one aspect of the invention there is provided a starter kit for titrating a patient diagnosed with hyperlipidemia with sustained release nicotinic acid compositions comprising: (a) 7 375 mg nicotinic acid sustained release tablets; (b) 7 500 mg nicotinic acid sustained release tablets; (c) 7 750 mg nicotinic acid sustained release tablets; and a housing for containing said tablets.
In accordance with another aspect of the invention there is provided a combination of sustained release nicotinic acid tablets for use to titrate a patient diagnosed with hyperlipidemia, wherein said tablets each provide a single dose for administration only once a day during the evening or at night as follows:375 mg of nicotinic acid in a sustained release formulation each day for 7 days, 500 mg nicotinic acid in a sustained release formulation each day for 7 days, and 750 mg nicotinic acid in a sustained release formulation each day for 7 days.
In accordance with yet another aspect of the invention there is provided the use of sustained release nicotinic acid tablets in the manufacture of a medicament to titrate a patient diagnosed with hyperlipidemia, the medicament providing the tablets so as to provide a single dose for administration only once a day during the evening or at night as follows: 375 mg of nicotinic acid in a sustained release formulation each day for 7 days, 500 mg nicotinic acid in a sustained release formulation each day for 7 days, and 750 mg nicotinic acid in a sustained release formulation each day for 7 days.
-4-In accordance with still another aspect of the invention there is provided a pharmaceutical formulation comprising a plurality of sustained release nicotinic acid tablets to titrate a patient diagnosed with hyperlipidemia, wherein said tablets comprise: (a) 7 375 mg nicotinic acid sustained release tablets; (b) 7 500 mg nicotinic acid sustained release tablets;
and (c) 7 750 mg nicotinic acid sustained release tablets.
These different aspects of the invention may further include:
(a) 1000 mg of sustained release nicotinic acid for administration as a single dose once daily during the evening or at night for approximately 30 days;
(b) 1500 mg of sustained release nicotinic acid for administration as a single dose once daily during the evening or at night for approximately 30 days;
(c) 2000 mg of sustained release nicotinic acid for administration as a single dose once daily during the evening or at night for approximately 30 days;
(d) 2500 mg of sustained release nicotinic acid for administration as a single dose once daily during the evening or at night for approximately 30 days, and (e) 3000 mg for administration thereafter.
In brief, the present invention alleviates and overcomes certain of the above-identified problems and shortcomings of the present state of nicotinic acid therapy through the discovery of novel nicotinic acid formulations and methods of treatment.
The present invention seeks to provide a composition of nicotinic acid or any compound which is metabolized by the body to form nicotinic acid for treating hyperlipidemia.
The present invention also seeks to provide a composition as above, which has a time release sustaining characteristic.
DOCSMTL: 1934481 \ 1 - 4a-The present invention further seeks to provide a method for employing a composition as above, for treating hyperlipidemia, which results in little or no liver damage.
At least one or more of the foregoing objectives, together with the advantages thereof over the known art relating to the treatment of hyperlipidemia, which shall become apparent from the specification which follows, are accomplished by the invention as hereinafter described.
In other aspects the present invention provides an improved antihyperlipidemia composition of the oral type employing an effective antihyperlipidemic amount of nicotinic acid, wherein the improvement comprises compounding the nicotinic acid with from about
and (c) 7 750 mg nicotinic acid sustained release tablets.
These different aspects of the invention may further include:
(a) 1000 mg of sustained release nicotinic acid for administration as a single dose once daily during the evening or at night for approximately 30 days;
(b) 1500 mg of sustained release nicotinic acid for administration as a single dose once daily during the evening or at night for approximately 30 days;
(c) 2000 mg of sustained release nicotinic acid for administration as a single dose once daily during the evening or at night for approximately 30 days;
(d) 2500 mg of sustained release nicotinic acid for administration as a single dose once daily during the evening or at night for approximately 30 days, and (e) 3000 mg for administration thereafter.
In brief, the present invention alleviates and overcomes certain of the above-identified problems and shortcomings of the present state of nicotinic acid therapy through the discovery of novel nicotinic acid formulations and methods of treatment.
The present invention seeks to provide a composition of nicotinic acid or any compound which is metabolized by the body to form nicotinic acid for treating hyperlipidemia.
The present invention also seeks to provide a composition as above, which has a time release sustaining characteristic.
DOCSMTL: 1934481 \ 1 - 4a-The present invention further seeks to provide a method for employing a composition as above, for treating hyperlipidemia, which results in little or no liver damage.
At least one or more of the foregoing objectives, together with the advantages thereof over the known art relating to the treatment of hyperlipidemia, which shall become apparent from the specification which follows, are accomplished by the invention as hereinafter described.
In other aspects the present invention provides an improved antihyperlipidemia composition of the oral type employing an effective antihyperlipidemic amount of nicotinic acid, wherein the improvement comprises compounding the nicotinic acid with from about
5% to about 50% parts by weight of hydroxypropyl methylcellulose per hundred parts by weight of tablet or formulation.
The present invention also provides an orally administered antihyperlipidemia composition which comprises from about 30% to about 90% parts by weight of nicotinic acid;
and, from about 5% to about 50% parts by weight of hydroxypropyl methylcellulose.
The present invention also includes a method of treating hyperlipidemia in a hyperlipidemic. The method comprises the steps of forming a composition which comprises an effective antihyperlipidemic amount of nicotinic acid and an amount of excipients to provide sustained release of drug. The method also includes the step of orally administering the composition to the hyperlipidemic nocturnally.
A method of treating hyperlipidemia in a hyperlipidemic according to the invention, comprises dosing the hyperlipidemic with an effective antihyperlipidemic amount of nicotinic acid or compound metabolized to nicotinic acid by the body. The dose is given once per day in the evening or at night, combined with a pharmaceutically acceptable carrier to produce a significant reduction in total and LDL cholesterol as well as a DOCSMTL: 1934481\1 significant reduction in triglycerides and Lp(a), with a significant increase in HDL
cholesterol.
The above features and advantages of the present invention will be better understood with reference to the following detailed description and examples. It should also be understood that the particular methods and formulations illustrating the present invention are exemplary only and not to be regarded as limitations of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
By way of illustrating and providing a more complete appreciation of the present invention and many of the attendant advantages thereof, the following detailed description and examples are given concerning the novel methods and formulations.
The present invention employs nicotinic acid or a compound other than nicotinic acid itself which the body metabolizes into nicotinic acid, thus producing the same effect as described herein. The other compounds specifically include, but are not limited to the following:
nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol and d, 1 -alpha-tocopheryl nicotinate. Each such compound will be collectively referred to hereinbelow by "nicotinic acid."
DOCSMTL: 1934481\1 i i
The present invention also provides an orally administered antihyperlipidemia composition which comprises from about 30% to about 90% parts by weight of nicotinic acid;
and, from about 5% to about 50% parts by weight of hydroxypropyl methylcellulose.
The present invention also includes a method of treating hyperlipidemia in a hyperlipidemic. The method comprises the steps of forming a composition which comprises an effective antihyperlipidemic amount of nicotinic acid and an amount of excipients to provide sustained release of drug. The method also includes the step of orally administering the composition to the hyperlipidemic nocturnally.
A method of treating hyperlipidemia in a hyperlipidemic according to the invention, comprises dosing the hyperlipidemic with an effective antihyperlipidemic amount of nicotinic acid or compound metabolized to nicotinic acid by the body. The dose is given once per day in the evening or at night, combined with a pharmaceutically acceptable carrier to produce a significant reduction in total and LDL cholesterol as well as a DOCSMTL: 1934481\1 significant reduction in triglycerides and Lp(a), with a significant increase in HDL
cholesterol.
The above features and advantages of the present invention will be better understood with reference to the following detailed description and examples. It should also be understood that the particular methods and formulations illustrating the present invention are exemplary only and not to be regarded as limitations of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
By way of illustrating and providing a more complete appreciation of the present invention and many of the attendant advantages thereof, the following detailed description and examples are given concerning the novel methods and formulations.
The present invention employs nicotinic acid or a compound other than nicotinic acid itself which the body metabolizes into nicotinic acid, thus producing the same effect as described herein. The other compounds specifically include, but are not limited to the following:
nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol and d, 1 -alpha-tocopheryl nicotinate. Each such compound will be collectively referred to hereinbelow by "nicotinic acid."
DOCSMTL: 1934481\1 i i
-6-As stated hereabove, nicotinic acid has been employed in the past for the treatment of hyperlipidemia, which condition is characterized by the presence of excess fats such as cholesterol and triglycerides, in the blood stream. According to the present invention, a sustained release composition of nicotinic acid is prepared as an example. By "sustained release" it is understood to mean a composition which when orally administered to a patient to be treated, the active ingredient will be released for absorption into the blood stream over a period of time. For exampled, it is preferred that in a dosage of about 1500 milllgrams (hereinafter "mgs") of nicotinic acid, approximately 100 percent of the nicotinic acid will be released into the blood stream in about 4 to about 24 hours.
The specified sustained releases composition according to the present invention employs an effective antihyperlipidemic amount of nicotinic acid. By "effective antihyperlipidemic amount" it is understood to mean an amount which when orally administered to a patient to be treated, will have a beneficial effect upon the physiology of the patient, to include at least some lowering of total cholesterol, LDL cholesterol, triglycerides and Lp(a) and at least some increase in HDL cholesterol in the patient's blood stream. An exemplary effective antihyperlipidemic amount of nicotinic acid would be from about 250 mgs to about 3000 mgs of nicotinic acid to be administered according to the invention as will be more fully described hereinbelow. This amount will vary dependent upon a number of variables, including the psychological needs of the patient to be treated.
Preferably, there is also included in the sustained release composition according to the present invention, a swelling agent which is compounded with the nicotinic acid, such that when the composition is orally administered to the patient, the swelling agent will swell over time in the patient's gastrointestinal tract, and release the active nicotinic acid, or a compound which produces nicotinic acid into the gastrointestinal system for absorption into the blood stream, over
The specified sustained releases composition according to the present invention employs an effective antihyperlipidemic amount of nicotinic acid. By "effective antihyperlipidemic amount" it is understood to mean an amount which when orally administered to a patient to be treated, will have a beneficial effect upon the physiology of the patient, to include at least some lowering of total cholesterol, LDL cholesterol, triglycerides and Lp(a) and at least some increase in HDL cholesterol in the patient's blood stream. An exemplary effective antihyperlipidemic amount of nicotinic acid would be from about 250 mgs to about 3000 mgs of nicotinic acid to be administered according to the invention as will be more fully described hereinbelow. This amount will vary dependent upon a number of variables, including the psychological needs of the patient to be treated.
Preferably, there is also included in the sustained release composition according to the present invention, a swelling agent which is compounded with the nicotinic acid, such that when the composition is orally administered to the patient, the swelling agent will swell over time in the patient's gastrointestinal tract, and release the active nicotinic acid, or a compound which produces nicotinic acid into the gastrointestinal system for absorption into the blood stream, over
-7-a period of time. As is known in the art, such swelling agents and amounts thereof, may be preselected in order to control the time release of the active ingredient.
Such swelling agents include, but are not limited to, polymers such as sodium carboxymethylcellulose and ethylcellulose and waxes such as bees wax and natural materials such as gums and gelatins or mixtures of any of the above. Because the amount of the swelling agent will vary depending upon the nature of the agent, the time release needs of the patient and the like, it is preferred ot employ amounts of the agent which will accomplish the objects of the invention.
An exemplary and preferred swelling agent is hydroxypropyl methylcellulose, in an amount ranging from about 5% to about 50% parts by weight per 100 parts by weight of tablet or formulation. The preferred example will ensure a sustained time release over a period of approximately 4-24 hours as demonstrated by in vitro dissolution techniques known to the art.
A binder may also be employed in the present compositions. While any known binding material is useful in the present invention, it is preferred to employ a material such as one or more of a group of polymers having the repeating unit of 1-ethenyl-2-pyrrolidinone.
These polymers generally have molecular weights of between about 10,000 and 700,000, and are also known as "povidone".
Amounts of the binder material will of course, vary depending upon the nature of the binder and the amount of other ingredients of the composition. An exemplary amount of povidone in the present compositions would be from about 1% to about 5% by weight of povidone per 100 parts by weight of the total formulation.
Processing aids such as lubricants, including stearic acid, may also be employed, as is known in the art. An exemplary amout of stearic acid in the present compositions would be from about 0.5% to about 2.0% by weight per 100 parts by weight of tablet or formulation.
i i
Such swelling agents include, but are not limited to, polymers such as sodium carboxymethylcellulose and ethylcellulose and waxes such as bees wax and natural materials such as gums and gelatins or mixtures of any of the above. Because the amount of the swelling agent will vary depending upon the nature of the agent, the time release needs of the patient and the like, it is preferred ot employ amounts of the agent which will accomplish the objects of the invention.
An exemplary and preferred swelling agent is hydroxypropyl methylcellulose, in an amount ranging from about 5% to about 50% parts by weight per 100 parts by weight of tablet or formulation. The preferred example will ensure a sustained time release over a period of approximately 4-24 hours as demonstrated by in vitro dissolution techniques known to the art.
A binder may also be employed in the present compositions. While any known binding material is useful in the present invention, it is preferred to employ a material such as one or more of a group of polymers having the repeating unit of 1-ethenyl-2-pyrrolidinone.
These polymers generally have molecular weights of between about 10,000 and 700,000, and are also known as "povidone".
Amounts of the binder material will of course, vary depending upon the nature of the binder and the amount of other ingredients of the composition. An exemplary amount of povidone in the present compositions would be from about 1% to about 5% by weight of povidone per 100 parts by weight of the total formulation.
Processing aids such as lubricants, including stearic acid, may also be employed, as is known in the art. An exemplary amout of stearic acid in the present compositions would be from about 0.5% to about 2.0% by weight per 100 parts by weight of tablet or formulation.
i i
-8-Examples of various embodiments of the present invention will now be further illustrated with reference to the following examples.
General Experimental In order to demonstrate the effectiveness of the compositions and method of the present invention over known antihyperlipidemia compositions and methods heretofore known in the art, a number of substantially identical composition were prepared according to the disclosure hereinabove. The composition and ingredients and amounts are listed in TABLE 1 A hereinbelow.
TABLE IA
Test Tablet Composition Ingredient 375 m~ 500 mg 750 mg Nicotinic Acid 375.0 500.0 750.0 Hyroxypropyl 188.7 203.0 204.7 methylcellulose Povidone 12.9 17.2 25.9 Stearic Acid 5.8 7.3 9.9 TOTAL 582.4 mg 727.5 mg 990.5 mg The ingredients were compounded together to form a tablet. More specifically, Niaspan once-daily tablets in accordance with the present invention utilize a hydrophilic matrix controlled drug delivery system. This is a dynamic system composed of polymer wetting, polymer hydration and polymer disintegration/dissolution. The mechanism by which drug release is controlled depends on, for example, initial polymer wetting, expansion of the gel layer, tablet erosion and niacin solubility. After initial wetting, the hydrophyllic polymer starts to partially hydrate, forming a gel layer. As water permeates into the tablet increasing the thickness of the gel layer, drug diffuses out of the gel layer. As the outer layer of the tablet becomes fully hydrated it erodes. It is believed that this erosion results in additional drug release. The controlled release from this
General Experimental In order to demonstrate the effectiveness of the compositions and method of the present invention over known antihyperlipidemia compositions and methods heretofore known in the art, a number of substantially identical composition were prepared according to the disclosure hereinabove. The composition and ingredients and amounts are listed in TABLE 1 A hereinbelow.
TABLE IA
Test Tablet Composition Ingredient 375 m~ 500 mg 750 mg Nicotinic Acid 375.0 500.0 750.0 Hyroxypropyl 188.7 203.0 204.7 methylcellulose Povidone 12.9 17.2 25.9 Stearic Acid 5.8 7.3 9.9 TOTAL 582.4 mg 727.5 mg 990.5 mg The ingredients were compounded together to form a tablet. More specifically, Niaspan once-daily tablets in accordance with the present invention utilize a hydrophilic matrix controlled drug delivery system. This is a dynamic system composed of polymer wetting, polymer hydration and polymer disintegration/dissolution. The mechanism by which drug release is controlled depends on, for example, initial polymer wetting, expansion of the gel layer, tablet erosion and niacin solubility. After initial wetting, the hydrophyllic polymer starts to partially hydrate, forming a gel layer. As water permeates into the tablet increasing the thickness of the gel layer, drug diffuses out of the gel layer. As the outer layer of the tablet becomes fully hydrated it erodes. It is believed that this erosion results in additional drug release. The controlled release from this
-9-matrix delivery system can be modified depending on the type and molecular weight of hydrophilic polymer used.
A Niaspan formulation consists of Niacin, Methocel E l OM Premium, Povidone and Hystrene 5016 (stearic acid). Methocel E I OM Premium is utilized as a controlled-release agent in the Niaspan formulation. Methocel is a partly 0-methylated and O-(2-hydroxypropylated) cellulose and is available in several grades which vary in terms of viscosity and degree of substitution. Methocel is manufactured by Dow Chemical.
Povidone K90 is employed as a granulating/binding agent in a Niaspan formulation.
Providone is a synthetic polymer consisting of linear 1-vinyl-2-pyrrolidone groups, the degree ofpolymerization of which results in polymers of various molecular weights, or as indicated above.
It is characterized by its viscosity in aqueous solution, relative to that of water, expressed as a K-value, ranging from 10-120. Povidone K90 has an approximate molecular weight of 1,000,000.
Povidone is a hygroscopic, water soluble material. Povidone K90 present in a Niaspan formulation is manufactured by ISP (International Specialty Products).
Hystrene 5016 is utilized as an external lubricant in the Niaspan forumation. Hystrene 5016 is a mixture of stearic acid and palmitic acid. The content of stearic acid is not less than about 40.0%
and the sum of the two acids is not less than about 90.0%. Hystrene 5016 is manufactured by Witco.
Refer to Table IB
for Niaspan forumlation details.
Qualitatively, the four tablet strength formulations are identical. The major component of each formulation is a granulated mixture of Niacin, Methocel E I OM and Povidone K90. The granulation process improves compression properties.
i i
A Niaspan formulation consists of Niacin, Methocel E l OM Premium, Povidone and Hystrene 5016 (stearic acid). Methocel E I OM Premium is utilized as a controlled-release agent in the Niaspan formulation. Methocel is a partly 0-methylated and O-(2-hydroxypropylated) cellulose and is available in several grades which vary in terms of viscosity and degree of substitution. Methocel is manufactured by Dow Chemical.
Povidone K90 is employed as a granulating/binding agent in a Niaspan formulation.
Providone is a synthetic polymer consisting of linear 1-vinyl-2-pyrrolidone groups, the degree ofpolymerization of which results in polymers of various molecular weights, or as indicated above.
It is characterized by its viscosity in aqueous solution, relative to that of water, expressed as a K-value, ranging from 10-120. Povidone K90 has an approximate molecular weight of 1,000,000.
Povidone is a hygroscopic, water soluble material. Povidone K90 present in a Niaspan formulation is manufactured by ISP (International Specialty Products).
Hystrene 5016 is utilized as an external lubricant in the Niaspan forumation. Hystrene 5016 is a mixture of stearic acid and palmitic acid. The content of stearic acid is not less than about 40.0%
and the sum of the two acids is not less than about 90.0%. Hystrene 5016 is manufactured by Witco.
Refer to Table IB
for Niaspan forumlation details.
Qualitatively, the four tablet strength formulations are identical. The major component of each formulation is a granulated mixture of Niacin, Methocel E I OM and Povidone K90. The granulation process improves compression properties.
i i
-10-TABLE IB
Niaspan Tablet Formulations Niaspan Product 375mg Tablets 500mg Tablets 750mg Tablets 1000mg Tablets Formulation_ % Tablets Niacin 64.4 70.5 77.4 83.1 Methocel EIOM 7.4 8.1 8.9 9.5 Prcmium (Intragranular) 2.2 2.4 2.7 2.9 Providonc K90 Methocel E l OM
25.0 18.0 10.0 3.5 Prcmium (Extragranular) Hvstrcnc 5016 1.0 1.0 1.0 1.0 (Stcaric Acid) Tablc weight, mg 582.5 709.5 968.6 1203.6 Niaspan formulations are presented in white caplet shape tablets. Caplet dimensions differ with respect to product strength. The 375mg and 500mg Niaspan tablets are compressed with tooling measuring approximately 0.687" in length x 0.281 " by width. The length and width of the 750mg and 1000mg tooling measures approximately Ø750" x 0.320".
Target tablet weight and hardness dictate thickness across the four Niaspan products. The production of the Niaspan tablets will now be described generally as set forth below.
Niaspan Tablet Formulations Niaspan Product 375mg Tablets 500mg Tablets 750mg Tablets 1000mg Tablets Formulation_ % Tablets Niacin 64.4 70.5 77.4 83.1 Methocel EIOM 7.4 8.1 8.9 9.5 Prcmium (Intragranular) 2.2 2.4 2.7 2.9 Providonc K90 Methocel E l OM
25.0 18.0 10.0 3.5 Prcmium (Extragranular) Hvstrcnc 5016 1.0 1.0 1.0 1.0 (Stcaric Acid) Tablc weight, mg 582.5 709.5 968.6 1203.6 Niaspan formulations are presented in white caplet shape tablets. Caplet dimensions differ with respect to product strength. The 375mg and 500mg Niaspan tablets are compressed with tooling measuring approximately 0.687" in length x 0.281 " by width. The length and width of the 750mg and 1000mg tooling measures approximately Ø750" x 0.320".
Target tablet weight and hardness dictate thickness across the four Niaspan products. The production of the Niaspan tablets will now be described generally as set forth below.
-11-Niasnan Granulation Process Flow Chart Raw Materials Process Flow Equipment Niacin Granulate High shear granulator Providone K90 (Littleford FM130) Methocel E l OM
(intragranular) Purfied Water Dry Fluid bed drier (Glatt fluid bed drier) Parcel size reduction Mill (Kemutec Betagrind) Niaspan R Granulation Process Description Niaspan granulation raw materials are dispensed and granulated in a high shear granulator. The wet granules are sieved into a fluid bed drier and are dried.
When the drying process is complete, the granules are milled. Milling ensures uniform particle size distribution throughout the Niaspan granulation.
Niasoan Tablet Process Flow Chart Raw Materials Process Flow Equipment Niaspan Tablet Blend Methocel Blend Milled NiaspanO~ granules Blender E l OM with (Patterson-Kelley (l:xtragranular) extragranular Methocel E l OM and V-Blender) Hystrene Hystrene 5016 5016 (Stearic acid) i Niaspan Tablc Manufacture Compress Niaspan Tablet Blend Rotary tablet press Niaspan Tablet Process Description A Niaspan tablet blend is manufactured by blending the Niaspan granulation, extragranular Methocel ElOM and Hystrene 5016. The quantities of each Niaspang tablet blend i i
(intragranular) Purfied Water Dry Fluid bed drier (Glatt fluid bed drier) Parcel size reduction Mill (Kemutec Betagrind) Niaspan R Granulation Process Description Niaspan granulation raw materials are dispensed and granulated in a high shear granulator. The wet granules are sieved into a fluid bed drier and are dried.
When the drying process is complete, the granules are milled. Milling ensures uniform particle size distribution throughout the Niaspan granulation.
Niasoan Tablet Process Flow Chart Raw Materials Process Flow Equipment Niaspan Tablet Blend Methocel Blend Milled NiaspanO~ granules Blender E l OM with (Patterson-Kelley (l:xtragranular) extragranular Methocel E l OM and V-Blender) Hystrene Hystrene 5016 5016 (Stearic acid) i Niaspan Tablc Manufacture Compress Niaspan Tablet Blend Rotary tablet press Niaspan Tablet Process Description A Niaspan tablet blend is manufactured by blending the Niaspan granulation, extragranular Methocel ElOM and Hystrene 5016. The quantities of each Niaspang tablet blend i i
-12-component will depend on the particular Niaspan dose being manufactured (refer to Table IB).
A Niaspan tablet blend is compressed to form Niaspan tablets. Niaspan tablet physical properties will vary depending on the particular Niaspan dose being manufactured.
Production of Niaspan tablets will now be discussed in greater detail. The initial stage of manufacturing is the same for all four tablet strengths of Niaspan (375, 500, 750 and l 000mg). One batch of Niaspan granulation is comprised of four individual 40.0kg units of granulation which are processed separately, but under like conditions. The four individual granulations are sampled and tested individually and subsequently released for blending. The base granulation is not strength specific and may be used to manufacture any tablet strength of Niaspan .
The ingredients in the base granulation are set froth in Table IC below:
TABLE IC
Component Function Quantity per % per Quantity per kilogram kilogram 160.00 kg granulation (kg) granulation batch (kg) (%) Niacin, iJSP Drug Substance 0.87 87.00 139.20 Povidine, tJPS Binder F 0.03 3.00 4.80 Mcthocel USP, Controlled- 0.10 10.00 16.00 E 1 OM Premium Release Agent CR Grade Purified Water, Granulation 0.00' 0.00' 48 USP' Reagent I _F Total 160 'Purified Water, USP is used as granulation reagent and does not appear in the finished granulation.
Raw materials are quantatively dispensed into appropriately labeled double polyethylene-lined containers using calibrated scales. Purified Water, USP is dispensed into an appropriate vessel from which it is later pumped during the wet-massing operation.
A Littleford FM130 granulator is charged with approximately one half of the Niacin, USP
required for the process unit (-17.4 kg) followed by about 4.00kg of Methocel, USP EIOM
Premium CR Grade; about 1.20kg of Povidine, USP; and the balance of the Niacin, SP
(-17.40kg). The powder bed is dry mixed in the Littleford FM130 granulator, with choppers on, for approximately 1 minute. At the completion of the 1-minute pre-mix cycle, about 12.0 0.05kg
A Niaspan tablet blend is compressed to form Niaspan tablets. Niaspan tablet physical properties will vary depending on the particular Niaspan dose being manufactured.
Production of Niaspan tablets will now be discussed in greater detail. The initial stage of manufacturing is the same for all four tablet strengths of Niaspan (375, 500, 750 and l 000mg). One batch of Niaspan granulation is comprised of four individual 40.0kg units of granulation which are processed separately, but under like conditions. The four individual granulations are sampled and tested individually and subsequently released for blending. The base granulation is not strength specific and may be used to manufacture any tablet strength of Niaspan .
The ingredients in the base granulation are set froth in Table IC below:
TABLE IC
Component Function Quantity per % per Quantity per kilogram kilogram 160.00 kg granulation (kg) granulation batch (kg) (%) Niacin, iJSP Drug Substance 0.87 87.00 139.20 Povidine, tJPS Binder F 0.03 3.00 4.80 Mcthocel USP, Controlled- 0.10 10.00 16.00 E 1 OM Premium Release Agent CR Grade Purified Water, Granulation 0.00' 0.00' 48 USP' Reagent I _F Total 160 'Purified Water, USP is used as granulation reagent and does not appear in the finished granulation.
Raw materials are quantatively dispensed into appropriately labeled double polyethylene-lined containers using calibrated scales. Purified Water, USP is dispensed into an appropriate vessel from which it is later pumped during the wet-massing operation.
A Littleford FM130 granulator is charged with approximately one half of the Niacin, USP
required for the process unit (-17.4 kg) followed by about 4.00kg of Methocel, USP EIOM
Premium CR Grade; about 1.20kg of Povidine, USP; and the balance of the Niacin, SP
(-17.40kg). The powder bed is dry mixed in the Littleford FM130 granulator, with choppers on, for approximately 1 minute. At the completion of the 1-minute pre-mix cycle, about 12.0 0.05kg
-13-of Purified Water, USP are sprayed onto the powder bed at a rate of about 2.40 0.24kg/minute.
Immediately following the addition of the Purified Water, USP, the unit is granulated for about minutes.
The granulated unit is discharged into double polyethylene-lined containers and then 5 manually loaded into a Glatt bowl while being passed through a #4 mesh screen. The Glatt bowl is loaded into a Glatt TFO-60 fluid-bed drier with an inlet air temperature setting of about 70 Ct5 C. The unit is dried until a moisture level of <_ 1.0% is obtained as determined using a Computrac Moisture Analyzer, model MA5A. The dried granulation is discharged into appropriately labeled, double polyethylene-lined drums and reconciled.
The dried and reconciled granulation is passed through a Kemutec BetaGrind mill equipped with a 1.5mm screen and running at approximately 1500 RPM. The milled granulation is collected into appropriately labeled, double polyethylene-lined drums and reconciled. The milled granulation is sampled and tested by Quality Control and released prior to further processing.
The released granulation units are charged to a Patterson-Kelley 20 ft3 V-blender after which they are blended together for about 10 1 minutes and then discharged to appropriately labeled, double polyethylene-lined containers.
As stated above, Niaspan tablets are formulated from a common granulation which is blended with appropriate quantities of Methocel, USP EIOM Premium CR Grade and Stearic Acid, NF to achieve the final dosage formulation. Tables IA and IB describe the formulation for each Niaspan tablet strength, 375mg, 500mg, 750mg and 1000mg, respectively.
Also in accordance with the present invention, a starter kit is provided for initial dosing and titration of a patient with a sustained release formulation of the present invention. Such a kit may contain, for example, 21 tablets in total at variant strengths for administration over a 21 consecutive day period to minimize and avoid any hepatotoxic and flushing effects associated with and to improve tolerance of the therapy. More particularly, the starter kit may include 7 nicotinic acid sustained release tablets at 375 mg, 7 nicotinic acid sustained replace tablets at 500 mg and 7 nicotinic acid sustained release tablets at 750 mg accompanied with instruction to take one tablet per day during the evening or at night beginning with the 375 mg strength tablets until gone, followed by the 500 mg strength tablets until gone, which is then followed by the 750 mg tablets until gone.
i i
Immediately following the addition of the Purified Water, USP, the unit is granulated for about minutes.
The granulated unit is discharged into double polyethylene-lined containers and then 5 manually loaded into a Glatt bowl while being passed through a #4 mesh screen. The Glatt bowl is loaded into a Glatt TFO-60 fluid-bed drier with an inlet air temperature setting of about 70 Ct5 C. The unit is dried until a moisture level of <_ 1.0% is obtained as determined using a Computrac Moisture Analyzer, model MA5A. The dried granulation is discharged into appropriately labeled, double polyethylene-lined drums and reconciled.
The dried and reconciled granulation is passed through a Kemutec BetaGrind mill equipped with a 1.5mm screen and running at approximately 1500 RPM. The milled granulation is collected into appropriately labeled, double polyethylene-lined drums and reconciled. The milled granulation is sampled and tested by Quality Control and released prior to further processing.
The released granulation units are charged to a Patterson-Kelley 20 ft3 V-blender after which they are blended together for about 10 1 minutes and then discharged to appropriately labeled, double polyethylene-lined containers.
As stated above, Niaspan tablets are formulated from a common granulation which is blended with appropriate quantities of Methocel, USP EIOM Premium CR Grade and Stearic Acid, NF to achieve the final dosage formulation. Tables IA and IB describe the formulation for each Niaspan tablet strength, 375mg, 500mg, 750mg and 1000mg, respectively.
Also in accordance with the present invention, a starter kit is provided for initial dosing and titration of a patient with a sustained release formulation of the present invention. Such a kit may contain, for example, 21 tablets in total at variant strengths for administration over a 21 consecutive day period to minimize and avoid any hepatotoxic and flushing effects associated with and to improve tolerance of the therapy. More particularly, the starter kit may include 7 nicotinic acid sustained release tablets at 375 mg, 7 nicotinic acid sustained replace tablets at 500 mg and 7 nicotinic acid sustained release tablets at 750 mg accompanied with instruction to take one tablet per day during the evening or at night beginning with the 375 mg strength tablets until gone, followed by the 500 mg strength tablets until gone, which is then followed by the 750 mg tablets until gone.
i i
-14-Once the starter kit has been completed, the patient should be further titrated by starting the patient on the following regimen in which the nicotinic acid sustained release tablets are administered as a single dose only once a day during the evening or at night:
2 x 500 mg tablets for one month;
2 x 750 mg tablets for one month;
2 x 1000 mg tablets for one month;
5 x 500 mg tablets for one month;
3 x 1000 mg tablets thereafter.
It of course should be understood, that after each dosage increase following completion of the starter kit as indicated above, the patient' lipid and liver enzyme profiles should be thoroughly examined to ensure that the patient is tolerating such therapy. In addition, the patient's lipid and liver enzyme profiles should be thoroughly checked before and upon completion of the starter kit, and that they should be continually and closely monitored throughout the entire therapeutic treatment.
It therefore should be appreciated by those versed in this art that the above-regimen represents one example as to how to titrate and treat a patient with hyperlipidemia in accordance with the present invention.
Two study groups consisting of eleven and fourteen patients each were formed.
Blood samples were taken from the patients, and tested for total cholesterol, LDL
cholesterol, triglycerides and HDL cholesterol to establish baseline levels from which fluctuations in these lipids could be compared. The patients were then placed upon a regimen of the above discussed tablets, totaling approximately 1500 mg of nicotinic acid, once per day before going to bed. After eight weeks of this regimen, the patients were again tested for lipid profiles. The results of tests conducted at eight weeks, showing the changes in the lipid profiles as a percentage change from the baseline, are reported in the table hereinbelow. Positive numbers reflect percentage increases and negative numbers reflect percentage decreases in this table.
2 x 500 mg tablets for one month;
2 x 750 mg tablets for one month;
2 x 1000 mg tablets for one month;
5 x 500 mg tablets for one month;
3 x 1000 mg tablets thereafter.
It of course should be understood, that after each dosage increase following completion of the starter kit as indicated above, the patient' lipid and liver enzyme profiles should be thoroughly examined to ensure that the patient is tolerating such therapy. In addition, the patient's lipid and liver enzyme profiles should be thoroughly checked before and upon completion of the starter kit, and that they should be continually and closely monitored throughout the entire therapeutic treatment.
It therefore should be appreciated by those versed in this art that the above-regimen represents one example as to how to titrate and treat a patient with hyperlipidemia in accordance with the present invention.
Two study groups consisting of eleven and fourteen patients each were formed.
Blood samples were taken from the patients, and tested for total cholesterol, LDL
cholesterol, triglycerides and HDL cholesterol to establish baseline levels from which fluctuations in these lipids could be compared. The patients were then placed upon a regimen of the above discussed tablets, totaling approximately 1500 mg of nicotinic acid, once per day before going to bed. After eight weeks of this regimen, the patients were again tested for lipid profiles. The results of tests conducted at eight weeks, showing the changes in the lipid profiles as a percentage change from the baseline, are reported in the table hereinbelow. Positive numbers reflect percentage increases and negative numbers reflect percentage decreases in this table.
-15-TABLE II
Patient Study Lipid Profile Data Pt. No. Total-C LDL-C Apo 13 Trias 1-IDI,-C HDL.-C LD(a) GROUP A
1 -8.2 -12.0 NA -17.3 22.0 NA NA
2 -5.9 -27.0 NA -28.7 65.0 NA NA
3 -15. I -13.0 NA -22 0 -9.1 NA NA
4 -3.3 -10.0 NA 61.6 3.8 NA NA
5 -16.5 -17.7 NA -28.8 11.1 NA NA
6 -12.4 -25.9 NA -42.0 51.6 NA NA
7 -24.2 -31.4 NA -39.4 12.5 NA NA
8 -6.7 -7.4 NA -42.4 18.8 NA NA
9 4.5 1.1 NA 7.2 9.2 NA NA
10 2.8 -0.2 NA -2.7 22.9 NA NA
11 -13.0 -9.4 NA -54.0 44.3 NA NA
Mean -8.9 -13.9 NA -18.9 23.0 NA NA
p-Value 0.0004-8.9 0.0001- 0.0371 0.0068 13.9 GROUP II
1 -19.2 -27.1 -24.4 -33.4 20.0 22.3 -81.9 2 -32.2 -35.7 -28.0 -60.4 4.3 3.2 -25.3 3 -21.4 -33.6 -35.6 -33.4 30.4 38.6 -17.4 4 -19.9 -24.6 -15.1 -20.8 9.6 16.1 -27.0 5 -3.3 -2.1 -29.4 -41.1 5.8 2.4 -22.4 7 23.1 -32.6 -42.6 -58.6 49.2 68.9 -14.3 8 24.8 34.0 -28.4 5.5 6.5 -6.8 NA
9 10.1 12.0 -16.8 -11.6 20.7 -12.3 40.6 10 -2.9 -7.7 -28.0 -59.0 53.1 70.5 -41.2 11 -10.5 -18.8 -25.3 -53.4 31.8 39.7 NA
12 -20.0 -30.8 -30.4 11.7 21.1 25.0 -28.4 13 17.4 16.8 -17.5 -17.5 51.3 51.9 38.5 i i
Patient Study Lipid Profile Data Pt. No. Total-C LDL-C Apo 13 Trias 1-IDI,-C HDL.-C LD(a) GROUP A
1 -8.2 -12.0 NA -17.3 22.0 NA NA
2 -5.9 -27.0 NA -28.7 65.0 NA NA
3 -15. I -13.0 NA -22 0 -9.1 NA NA
4 -3.3 -10.0 NA 61.6 3.8 NA NA
5 -16.5 -17.7 NA -28.8 11.1 NA NA
6 -12.4 -25.9 NA -42.0 51.6 NA NA
7 -24.2 -31.4 NA -39.4 12.5 NA NA
8 -6.7 -7.4 NA -42.4 18.8 NA NA
9 4.5 1.1 NA 7.2 9.2 NA NA
10 2.8 -0.2 NA -2.7 22.9 NA NA
11 -13.0 -9.4 NA -54.0 44.3 NA NA
Mean -8.9 -13.9 NA -18.9 23.0 NA NA
p-Value 0.0004-8.9 0.0001- 0.0371 0.0068 13.9 GROUP II
1 -19.2 -27.1 -24.4 -33.4 20.0 22.3 -81.9 2 -32.2 -35.7 -28.0 -60.4 4.3 3.2 -25.3 3 -21.4 -33.6 -35.6 -33.4 30.4 38.6 -17.4 4 -19.9 -24.6 -15.1 -20.8 9.6 16.1 -27.0 5 -3.3 -2.1 -29.4 -41.1 5.8 2.4 -22.4 7 23.1 -32.6 -42.6 -58.6 49.2 68.9 -14.3 8 24.8 34.0 -28.4 5.5 6.5 -6.8 NA
9 10.1 12.0 -16.8 -11.6 20.7 -12.3 40.6 10 -2.9 -7.7 -28.0 -59.0 53.1 70.5 -41.2 11 -10.5 -18.8 -25.3 -53.4 31.8 39.7 NA
12 -20.0 -30.8 -30.4 11.7 21.1 25.0 -28.4 13 17.4 16.8 -17.5 -17.5 51.3 51.9 38.5 i i
-16-TABLE II (Continued) Patient Study Lipid Profile Data Pt. No. Total-C I,DL-C Apo B Tries HDL-C HDL.-C Ln(al 14 -9.4 -16.6 -32.0 -46.9 52.3 67.6 17.6 MEAN -8.7 -12.8 -32.2 -27.2 25.3 30.1 -17.9 p-Value 0.0002 <0.0001 0.0001 <0.001 <0.0001 0.0002 <0.0188 Combined -8.7 -13.3 Gp 13 -26.1 25.3 Gp B Gp 13 p-Value 0.0002 <0.0001 only <.0001 <0.0001 only oniy The data reported in Table II shows that the LDL levels in the Group A
patients had a mean decrease of -13.9% and triglyceride decrease of -18.9% HDL cholesterol levels, the beneficial cholesterol, were raised by 23.0% in this Group. Similar results were obtained with the Group B patients. These studies demonstrate that dosing the sustained release formulation during the evening hours or at night provides reductions in LDL cholesterol levels equal to immediate release niacin on a milligram per milligram basis, but superior reductions in triglyceride reduction when compared to sustained release formulations dosed during daytime hours on a milligram per milligram basis. Additionally, the increases in HDL cholesterol obtained from dosing the sustained release formulation during the evening or at night were +23.0% for one group and +25.3% for the other group. Dosing during the evening therefore provides reduction in LDL
cholesterol plus significant decreases in triglycerides and increases in HDL
cholesterol with once-a-day dosing.
Groups A and B were also tested for liver enzymes (AST, ALT and Alkaline Phosphatase), uric acid and fasting glucose levels at the start of the study described hereinabove (to form a baseline) and at two, four and eight week intervals. The results of these tests are listed in TABLES III-VII hereinbelow.
patients had a mean decrease of -13.9% and triglyceride decrease of -18.9% HDL cholesterol levels, the beneficial cholesterol, were raised by 23.0% in this Group. Similar results were obtained with the Group B patients. These studies demonstrate that dosing the sustained release formulation during the evening hours or at night provides reductions in LDL cholesterol levels equal to immediate release niacin on a milligram per milligram basis, but superior reductions in triglyceride reduction when compared to sustained release formulations dosed during daytime hours on a milligram per milligram basis. Additionally, the increases in HDL cholesterol obtained from dosing the sustained release formulation during the evening or at night were +23.0% for one group and +25.3% for the other group. Dosing during the evening therefore provides reduction in LDL
cholesterol plus significant decreases in triglycerides and increases in HDL
cholesterol with once-a-day dosing.
Groups A and B were also tested for liver enzymes (AST, ALT and Alkaline Phosphatase), uric acid and fasting glucose levels at the start of the study described hereinabove (to form a baseline) and at two, four and eight week intervals. The results of these tests are listed in TABLES III-VII hereinbelow.
-17-TABLE III
THE EFFECT OF NIASPAN THERAPY ON AST (SGOT) LEVELS (U/L) (1500 mgs dosed once-a-day at night) (n=28) Weeks of Therapy With Niaspan ~t# Baseline 2 Wks. 4 Wks. 8 Wks. Reference Ranae GROUP A
GROUP B
6 PATIENT WITI-IDRI:W DUE TO FLUSHING
i i
THE EFFECT OF NIASPAN THERAPY ON AST (SGOT) LEVELS (U/L) (1500 mgs dosed once-a-day at night) (n=28) Weeks of Therapy With Niaspan ~t# Baseline 2 Wks. 4 Wks. 8 Wks. Reference Ranae GROUP A
GROUP B
6 PATIENT WITI-IDRI:W DUE TO FLUSHING
i i
-18-TABLE III (Continued) THE EFFECT OF NIASPAN THERAPY ON AST (SGOT) LEVELS (U/L) (1500 mgs dosed once-a-day at night) (n = 28) Weeks of Therapy With Niaspan Pt# Baseline 2 Wks. 4 Wks. 8 Wks. Reference Ranae Comhined Mean 19.8 20.4 20.8 21.1 Change From +3.0% +5.1 % +0.6%
Baseline Level of Significancc: p=0.4141 TABLE IV
THE EFFECT OF NIASPAN THERAPY ON ALT (SGPT) LEVELS (U/L) (1500 mgs dosed once-a-day at night) (n = 28) Weeks of Therapy With Niaspan Pt# Baseline 2 Wks, 4 Wks. 8 Wks, Reference Range GROUP A
Baseline Level of Significancc: p=0.4141 TABLE IV
THE EFFECT OF NIASPAN THERAPY ON ALT (SGPT) LEVELS (U/L) (1500 mgs dosed once-a-day at night) (n = 28) Weeks of Therapy With Niaspan Pt# Baseline 2 Wks, 4 Wks. 8 Wks, Reference Range GROUP A
-19-TABLE IV (Continued) THE EFFECT OF NIASPAN THERAPY ON ALT (SGPT) LEVELS (U/L) (1500 mgs dosed once-a-day at night) (n = 28) Weeks of Therapy With Niaspan 15 PI# Baselin 2 Wks. 4 Wks. 8 Wks. Reference Range GROUP B
Combined 17.7 17.5 19.3 18.2 Mean Change -1.1% 9.0% +2.8%
From Baseline Level of Significance: p=0.3424 i i
Combined 17.7 17.5 19.3 18.2 Mean Change -1.1% 9.0% +2.8%
From Baseline Level of Significance: p=0.3424 i i
-20-TABLE V
THE EFFECT OF NIASPAN THERAPY
ON ALKALINE PHOSPHATASE LEVELS (U/L) (1500 mgs dosed once-a-day at night) (n = 28) Weeks of Therapy With Niaspan Baseline 2 Wks 4 Wks 8 Wks Reference Range GROUP A
GROUP B
THE EFFECT OF NIASPAN THERAPY
ON ALKALINE PHOSPHATASE LEVELS (U/L) (1500 mgs dosed once-a-day at night) (n = 28) Weeks of Therapy With Niaspan Baseline 2 Wks 4 Wks 8 Wks Reference Range GROUP A
GROUP B
-21-TABLE V (Continued) THE EFFECT OF NIASPAN THERAPY
ON ALKALINE PHOSPHATASE LEVELS (U/L) (1500 mgs dosed once-a-day at night) (n = 28) Weeks of Therapy With Niaspan Pt# Baseline 2 Wks 41W Wks 8 Wks Reference Range Combined 66.5 61.5 63.3 65.8 Mean Change -6.1% -3.4% +0.005%
From 10 Baseline Level of Significance~ p=0.0236 i i
ON ALKALINE PHOSPHATASE LEVELS (U/L) (1500 mgs dosed once-a-day at night) (n = 28) Weeks of Therapy With Niaspan Pt# Baseline 2 Wks 41W Wks 8 Wks Reference Range Combined 66.5 61.5 63.3 65.8 Mean Change -6.1% -3.4% +0.005%
From 10 Baseline Level of Significance~ p=0.0236 i i
-22-TABLE VI
THE EFFECT OF NIASPAN THERAPY ON URIC ACID LEVELS (mg/dL) (1500 mgs dosed once-a-day at night) (n=28) Weeks of Therapy With Niaspan Pt# Baseline 2 Wks, 4 Wks= 8 Wks. Reference Range GROUP A
1 5.2 5.0 4.8 4.3 4.0-8.5 2 4.0 4.6 4.5 6.2 2.5-7.5 3 6.3 7.0 6.5 6.2 4.0-8.5 4 3.1 4.6 4.2 3.8 2.5-7.5 5 3.4 NA 3.3 4.2 2.5-7.5 6 6.6 5.5 5.6 4.7 4.0-8.5 7 3.8 4.5 4.3 4.9 2.5-7.5 8 4.4 3.8 5.1 4.5 2.5-7.5 9 3.9 4.5 4.6 3.5 2.5-7.5 10 2.6 2.9 2.8 2.7 2.5-7.5 11 4.7 5.5 5.2 5.3 2.5-7.5 GROUP B
1 3.7 4.2 4.7 3.5 2.5-7.5 2 2.8 3.5 3.6 2.3 4.0-8.5 3 4.2 5.3 5.5 5.3 2.5-7.5 4 4.7 3.9 5.1 3.6 4.0-8.5 5 3.7 4.1 4.1 3.8 2.5-7.5 7 5.8 6.6 6.6 6.8 2.5-7.5 8 4.7 4.3 5.4 5.6 2.5-7.5 9 3.7 4.6 5.1 3.8 2.5-7.5
THE EFFECT OF NIASPAN THERAPY ON URIC ACID LEVELS (mg/dL) (1500 mgs dosed once-a-day at night) (n=28) Weeks of Therapy With Niaspan Pt# Baseline 2 Wks, 4 Wks= 8 Wks. Reference Range GROUP A
1 5.2 5.0 4.8 4.3 4.0-8.5 2 4.0 4.6 4.5 6.2 2.5-7.5 3 6.3 7.0 6.5 6.2 4.0-8.5 4 3.1 4.6 4.2 3.8 2.5-7.5 5 3.4 NA 3.3 4.2 2.5-7.5 6 6.6 5.5 5.6 4.7 4.0-8.5 7 3.8 4.5 4.3 4.9 2.5-7.5 8 4.4 3.8 5.1 4.5 2.5-7.5 9 3.9 4.5 4.6 3.5 2.5-7.5 10 2.6 2.9 2.8 2.7 2.5-7.5 11 4.7 5.5 5.2 5.3 2.5-7.5 GROUP B
1 3.7 4.2 4.7 3.5 2.5-7.5 2 2.8 3.5 3.6 2.3 4.0-8.5 3 4.2 5.3 5.5 5.3 2.5-7.5 4 4.7 3.9 5.1 3.6 4.0-8.5 5 3.7 4.1 4.1 3.8 2.5-7.5 7 5.8 6.6 6.6 6.8 2.5-7.5 8 4.7 4.3 5.4 5.6 2.5-7.5 9 3.7 4.6 5.1 3.8 2.5-7.5
-23-TABLE VI (Continued) THE EFFECT OF NIASPAN THERAPY ON URIC ACID LEVELS (mg/dL) (1500 mgs dosed once-a-day at night) (n = 28) Weeks of Therapy With Niaspan PL# Baseline 2 Wks. 4 Wks. 8 Wks. Reference Range 4.2 5.0 4.4 8.5 2.5-7.5 11 1.9 3.0 2.8 5.0 2.5-7.5 12 5.6 5.4 6.2 5.6 4.0-8.5 13 4.2 4.6 4.6 5.3 2.5-7.5 5 14 5.5 5.4 6.1 5.3 2.5-7.5 Combined 4.54 4.82 4.92 4.86 *p=0.3450 Mean Change +6.2% +8.4% +7.0%
From 10 Baseline *Level of Significance: p=0.3450 i i
From 10 Baseline *Level of Significance: p=0.3450 i i
-24-TABLE VII
THE EFFECT OF NIASPAN THERAPY
ON FASTING GLUCOSE LEVELS (mg/dL) (n = 28) Weeks of Therapy With Niaspan Pt# Baseline 2 Wks 4 Wks. 8 Wks Reference Rage GROUP A
GROUP B
THE EFFECT OF NIASPAN THERAPY
ON FASTING GLUCOSE LEVELS (mg/dL) (n = 28) Weeks of Therapy With Niaspan Pt# Baseline 2 Wks 4 Wks. 8 Wks Reference Rage GROUP A
GROUP B
-25-TABLE VII (Continued) THE EFFECT OF NIASPAN THERAPY
ON FASTING GLUCOSE LEVELS (mg/dL) (n = 28) Weeks of Therapy With Niaspan Pt# Baseline 2 Wks 4 Wks. 8 Wks Reference Range Combined 98.4 105 . 8 101.6 102.3 Mean Change From +7.5% +3.3% +4.0%
Baseline Level of Significance: p=0.0021 In order to provide a comparison between the state of the art formulations prior to the present invention, and in order to quantify the magnitude of the improvement that the sustained release formulations described above provide over the prior art formulations, another study was conducted. This study included 240 patients dosed with the sustained release formulations as described hereinabove. Compared to this group was the group of patients studied by McKenney et al, as reported hereinabove. The results of this study are reported in TABLE VIII hereinbelow.
A Comparison of Changes in Liver Function Tests DOSE
_ F 0 500 1000 1500 2000 2500 3000 TOTAI.
McKenney Srb _ Niacin' I I F I AST 23.8 27.9 I 40.4 36.6 56 5 na 97 0 y % -- 117 170 154 237 na 408 Invention Dosage' i w N N
AST F 24.3 na 23.7 17.5 26.6 276 ' 27.8 ~-% -- na 98 113 109 114 114 McKenney SR
Niacin F
ALT 725.6 29.5 36.3 39.0 59.1 ~ NA 100.0 % F -- 115 142 152 231 NA 391 Invention Dosage ALT F 21.4 na 18.7 F 22.6 ~ 21.3 22,4 21 8 % -- na 87 106 100 105 102 McKenney SR
Niacin o ALK 95 95 106 105 136 na 135 00 TABLE VIII (Continued) A Comparison of Changes in Liver Funciion Tests 00 DOSE
% F 100 112 lII 143 na 112 Invention Dosage 1 ALK 74.7 na 73.9 76.1 73 4 76 7 78 0 % na 99 102 98 103 10=1 W
McKenney SR
Niacin F
JDrop r~ -- 0 I 2 4 na 5 12 o Fn !~~ 23 0 1% ~~1 0 4 9 17 na 22 52 Invention Dosage ~ ~
Drop ~- -- 0 0 0 0 0 0 I n F ---1 26 67 97 35 15 240 % F- -- 0 0 0 0 0 10 1 15 46 77 31 Is 184 year oo year F oA
~
ao ' Dosed twice-per-day as described in "A Comparison of the Efficacy and Toxic Effects of Sustained - vs Immediate - Release.Niacin in Hypercholesterolemic. Patients"
by McKenney et al.
Journal of the American Medical Association, March 2, 1994; Vol. 271, No. 9, pages 672-677.
SR is "sustained release"
' Dosed once-per-day at night The results of the comparison of the studies reported in Table VIII show that the control group (the McKenney group) had 12 of 23, or 52 percent of the patients therein drop out of the test because of an increase in their respective liver function tests. The patients withdrew at the direction of the investigator. In comparison, a group of 240 patients treated with the sustained release formulations described hereinbefore and which may be employed in the present invention had zero patients drop out, based upon the same criteria for withdrawal.
The test results reported above indicate that this sustained release dosage form caused no elevation in liver function tests (i.e., no liver damage), no elevations in uric acid and only a small, 7.5% increase in fasting glucose levels which in fact decreased during continued therapy.
Thus it should be evident that the sustained release formulations described hereinbefore are highly effective in controlling hyperlipidemia in hyperlipidemics, by reducing the levels of LDL cholesterol, triglyceride and Lp(a) while increasing HDL
cholesterol levels. The sustained release formulations described hereinbefore are also demonstrated not to cause elevations in liver function tests, uric acid or glucose levels for the hyperlipidemics.
Based upon the foregoing disclosure, it should now be apparent that the use of the compositions and methods described herein will carry out the objects set forth hereinabove. It is, therefore, to be understood that any variations in sustained release formulation evident fall within the scope of the claimed invention and thus, the selection of specific component elements can be determined without departing from the spirit of the invention herein disclosed and described. In particular, sustained release excipients, binders and processing aids according to the present. invention are not necessarily limited to those exemplified hereinabove. Thus, the scope of the invention shall include all modifications and variations that may fall within the scope of the attached claims.
ON FASTING GLUCOSE LEVELS (mg/dL) (n = 28) Weeks of Therapy With Niaspan Pt# Baseline 2 Wks 4 Wks. 8 Wks Reference Range Combined 98.4 105 . 8 101.6 102.3 Mean Change From +7.5% +3.3% +4.0%
Baseline Level of Significance: p=0.0021 In order to provide a comparison between the state of the art formulations prior to the present invention, and in order to quantify the magnitude of the improvement that the sustained release formulations described above provide over the prior art formulations, another study was conducted. This study included 240 patients dosed with the sustained release formulations as described hereinabove. Compared to this group was the group of patients studied by McKenney et al, as reported hereinabove. The results of this study are reported in TABLE VIII hereinbelow.
A Comparison of Changes in Liver Function Tests DOSE
_ F 0 500 1000 1500 2000 2500 3000 TOTAI.
McKenney Srb _ Niacin' I I F I AST 23.8 27.9 I 40.4 36.6 56 5 na 97 0 y % -- 117 170 154 237 na 408 Invention Dosage' i w N N
AST F 24.3 na 23.7 17.5 26.6 276 ' 27.8 ~-% -- na 98 113 109 114 114 McKenney SR
Niacin F
ALT 725.6 29.5 36.3 39.0 59.1 ~ NA 100.0 % F -- 115 142 152 231 NA 391 Invention Dosage ALT F 21.4 na 18.7 F 22.6 ~ 21.3 22,4 21 8 % -- na 87 106 100 105 102 McKenney SR
Niacin o ALK 95 95 106 105 136 na 135 00 TABLE VIII (Continued) A Comparison of Changes in Liver Funciion Tests 00 DOSE
% F 100 112 lII 143 na 112 Invention Dosage 1 ALK 74.7 na 73.9 76.1 73 4 76 7 78 0 % na 99 102 98 103 10=1 W
McKenney SR
Niacin F
JDrop r~ -- 0 I 2 4 na 5 12 o Fn !~~ 23 0 1% ~~1 0 4 9 17 na 22 52 Invention Dosage ~ ~
Drop ~- -- 0 0 0 0 0 0 I n F ---1 26 67 97 35 15 240 % F- -- 0 0 0 0 0 10 1 15 46 77 31 Is 184 year oo year F oA
~
ao ' Dosed twice-per-day as described in "A Comparison of the Efficacy and Toxic Effects of Sustained - vs Immediate - Release.Niacin in Hypercholesterolemic. Patients"
by McKenney et al.
Journal of the American Medical Association, March 2, 1994; Vol. 271, No. 9, pages 672-677.
SR is "sustained release"
' Dosed once-per-day at night The results of the comparison of the studies reported in Table VIII show that the control group (the McKenney group) had 12 of 23, or 52 percent of the patients therein drop out of the test because of an increase in their respective liver function tests. The patients withdrew at the direction of the investigator. In comparison, a group of 240 patients treated with the sustained release formulations described hereinbefore and which may be employed in the present invention had zero patients drop out, based upon the same criteria for withdrawal.
The test results reported above indicate that this sustained release dosage form caused no elevation in liver function tests (i.e., no liver damage), no elevations in uric acid and only a small, 7.5% increase in fasting glucose levels which in fact decreased during continued therapy.
Thus it should be evident that the sustained release formulations described hereinbefore are highly effective in controlling hyperlipidemia in hyperlipidemics, by reducing the levels of LDL cholesterol, triglyceride and Lp(a) while increasing HDL
cholesterol levels. The sustained release formulations described hereinbefore are also demonstrated not to cause elevations in liver function tests, uric acid or glucose levels for the hyperlipidemics.
Based upon the foregoing disclosure, it should now be apparent that the use of the compositions and methods described herein will carry out the objects set forth hereinabove. It is, therefore, to be understood that any variations in sustained release formulation evident fall within the scope of the claimed invention and thus, the selection of specific component elements can be determined without departing from the spirit of the invention herein disclosed and described. In particular, sustained release excipients, binders and processing aids according to the present. invention are not necessarily limited to those exemplified hereinabove. Thus, the scope of the invention shall include all modifications and variations that may fall within the scope of the attached claims.
Claims (7)
1. A starter kit for titrating a patient diagnosed with hyperlipidemia with sustained release nicotinic acid compositions comprising:
(a) 7 375 mg nicotinic acid sustained release tablets;
(b) 7 500 mg nicotinic acid sustained release tablets;
(c) 7 750 mg nicotinic acid sustained release tablets; and a housing for containing said tablets.
(a) 7 375 mg nicotinic acid sustained release tablets;
(b) 7 500 mg nicotinic acid sustained release tablets;
(c) 7 750 mg nicotinic acid sustained release tablets; and a housing for containing said tablets.
2. A combination of sustained release nicotinic acid tablets for use to titrate a patient diagnosed with hyperlipidemia, wherein said tablets each provide a single dose for administration only once a day during the evening or at night as follows:
375 mg of nicotinic acid in a sustained release formulation each day for 7 days, 500 mg nicotinic acid in a sustained release formulation each day for 7 days, and 750 mg nicotinic acid in a sustained release formulation each day for 7 days.
375 mg of nicotinic acid in a sustained release formulation each day for 7 days, 500 mg nicotinic acid in a sustained release formulation each day for 7 days, and 750 mg nicotinic acid in a sustained release formulation each day for 7 days.
3. A combination in accordance with claim 2, wherein said tablets further comprise:
(a) 1000 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for one month;
(b) 1500 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for one month;
(c) 2000 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for one month;
(d) 2500 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for one month; and (e) 3000 mg for administration thereafter.
(a) 1000 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for one month;
(b) 1500 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for one month;
(c) 2000 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for one month;
(d) 2500 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for one month; and (e) 3000 mg for administration thereafter.
4. The use of sustained release nicotinic acid tablets in the manufacture of a medicament to titrate a patient diagnosed with hyperlipidemia, the medicament comprising a plurality of the tablets so as to provide a single dose for administration only once a day during the evening or at night as follows:
375 mg of nicotinic acid in a sustained release formulation each day for 7 days, 500 mg nicotinic acid in a sustained release formulation each day for 7 days, and 750 mg nicotinic acid in a sustained release formulation each day for 7 days.
375 mg of nicotinic acid in a sustained release formulation each day for 7 days, 500 mg nicotinic acid in a sustained release formulation each day for 7 days, and 750 mg nicotinic acid in a sustained release formulation each day for 7 days.
5. The use in accordance with claim 4, wherein said medicament further comprises:
(a) 1000 mg of sustained release nicotinic acid for administration as a single dose once daily during the evening or at night for one month;
(b) 1500 mg of sustained release nicotinic acid for administration as a single dose once daily during the evening or at night for one month;
(c) 2000 mg of sustained release nicotinic acid for administration as a single dose once daily during the evening or at night for one month;
(d) 2500 mg of sustained release nicotinic acid for administration as a single dose once daily during the evening or at night for one month; and (e) 3000 mg for administration thereafter.
(a) 1000 mg of sustained release nicotinic acid for administration as a single dose once daily during the evening or at night for one month;
(b) 1500 mg of sustained release nicotinic acid for administration as a single dose once daily during the evening or at night for one month;
(c) 2000 mg of sustained release nicotinic acid for administration as a single dose once daily during the evening or at night for one month;
(d) 2500 mg of sustained release nicotinic acid for administration as a single dose once daily during the evening or at night for one month; and (e) 3000 mg for administration thereafter.
6. A pharmaceutical product comprising a plurality of sustained release nicotinic acid tablets to titrate a patient diagnosed with hyperlipidemia, wherein said plurality comprises:
(a) 7 375 mg nicotinic acid sustained release tablets;
(b) 7 500 mg nicotinic acid sustained release tablets; and (c) 7 750 mg nicotinic acid sustained release tablets.
(a) 7 375 mg nicotinic acid sustained release tablets;
(b) 7 500 mg nicotinic acid sustained release tablets; and (c) 7 750 mg nicotinic acid sustained release tablets.
7. A pharmaceutical product in accordance with claim 6, further comprising:
(a) tablets each providing 1000 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for one month;
(b) tablets each providing 1500 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for one month;
(c) tablets each providing 2000 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for one month;
(d) tablets each providing 2500 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for one month; and (e) tablets each providing 3000 mg thereafter.
(a) tablets each providing 1000 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for one month;
(b) tablets each providing 1500 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for one month;
(c) tablets each providing 2000 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for one month;
(d) tablets each providing 2500 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for one month; and (e) tablets each providing 3000 mg thereafter.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002591710A CA2591710A1 (en) | 1997-03-06 | 1998-03-06 | Starter kit containing nicotinic acid compositions |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US814,974 | 1997-03-06 | ||
| US08/814,974 US6129930A (en) | 1993-09-20 | 1997-03-06 | Methods and sustained release nicotinic acid compositions for treating hyperlipidemia at night |
| PCT/US1998/004578 WO1998039001A1 (en) | 1997-03-06 | 1998-03-06 | Starter kit containing nicotinic acid compositions |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002591710A Division CA2591710A1 (en) | 1997-03-06 | 1998-03-06 | Starter kit containing nicotinic acid compositions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2283322A1 CA2283322A1 (en) | 1998-09-11 |
| CA2283322C true CA2283322C (en) | 2007-06-19 |
Family
ID=25216509
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002283322A Expired - Lifetime CA2283322C (en) | 1997-03-06 | 1998-03-06 | Starter kit containing nicotinic acid compositions |
| CA002591710A Abandoned CA2591710A1 (en) | 1997-03-06 | 1998-03-06 | Starter kit containing nicotinic acid compositions |
| CA002283159A Expired - Lifetime CA2283159C (en) | 1997-03-06 | 1998-03-06 | Nicotinic acid compositions for treating hyperlipidemia and related methods therefor |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002591710A Abandoned CA2591710A1 (en) | 1997-03-06 | 1998-03-06 | Starter kit containing nicotinic acid compositions |
| CA002283159A Expired - Lifetime CA2283159C (en) | 1997-03-06 | 1998-03-06 | Nicotinic acid compositions for treating hyperlipidemia and related methods therefor |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US6129930A (en) |
| EP (2) | EP0966284B1 (en) |
| AT (1) | ATE289197T1 (en) |
| AU (2) | AU6348198A (en) |
| BR (2) | BR9815457A (en) |
| CA (3) | CA2283322C (en) |
| DE (1) | DE69829042T2 (en) |
| ES (1) | ES2234100T3 (en) |
| FI (2) | FI119910B (en) |
| NO (2) | NO994275L (en) |
| WO (2) | WO1998039002A1 (en) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6676967B1 (en) * | 1993-09-20 | 2004-01-13 | Kos Pharmaceuticals, Inc. | Methods for reducing flushing in individuals being treated with nicotinic acid for hyperlipidemia |
| US20060263428A1 (en) * | 1993-09-20 | 2006-11-23 | Eugenio Cefali | Methods for treating hyperlipidemia with intermediate release nicotinic acid compositions having unique biopharmaceutical characteristics |
| US20080045573A1 (en) * | 1993-09-20 | 2008-02-21 | Bova David J | Methods and Sustained Release Nicotinic Acid Compositions for Treating Hyperlipidemia |
| US6129930A (en) * | 1993-09-20 | 2000-10-10 | Bova; David J. | Methods and sustained release nicotinic acid compositions for treating hyperlipidemia at night |
| EP2319513A1 (en) * | 1993-09-20 | 2011-05-11 | Abbott Respiratory LLC | Nicotinic acid compositons for treating hyperlipidemia and related methods therefor |
| US6262115B1 (en) * | 1995-05-22 | 2001-07-17 | Alza Coporation | Method for the management of incontinence |
| US5912268A (en) * | 1995-05-22 | 1999-06-15 | Alza Corporation | Dosage form and method for treating incontinence |
| CA2298549C (en) * | 1997-07-31 | 2006-01-10 | Kos Pharmaceuticals, Inc. | Combinations of hmg-coa reductase inhibitors and nicotinic acid compounds and methods for treating hyperlipidemia once a day at night |
| US20010006644A1 (en) * | 1997-07-31 | 2001-07-05 | David J. Bova | Combinations of hmg-coa reductase inhibitors and nicotinic acid and methods for treating hyperlipidemia once a day at night |
| IL139450A0 (en) * | 1999-11-10 | 2001-11-25 | Pfizer Prod Inc | Methods of administering apo b-secretion/mtp inhibitors |
| AU2003222009A1 (en) * | 2002-03-18 | 2003-10-08 | Pharmacia Corporation | Combination of an aldosterone receptor antagonist and nicotinic acid or a nicotinic acid derivative |
| PL364348A1 (en) | 2004-01-12 | 2005-07-25 | PHARMENA Sp.z o.o. | Application of quaternary pyridine salts as vessel protection agent |
| KR100574554B1 (en) * | 2004-05-28 | 2006-04-27 | 한미약품 주식회사 | Sustained release composition for oral administration of niacin |
| AU2006329564A1 (en) | 2005-07-11 | 2007-07-05 | Pharmena North America Inc. | Formulations for treatment of lipoprotein abnormalities comprising a statin a statin and a methylnicotinamide derivative |
| CA2569776A1 (en) * | 2006-02-17 | 2007-08-17 | Kos Life Sciences, Inc. | Low flush niacin formulation |
| US20090069275A1 (en) * | 2006-02-17 | 2009-03-12 | Rocca Jose G | Low flush niacin formulation |
| AU2007223787A1 (en) * | 2006-03-08 | 2007-09-13 | Pharmena North America Inc. | Combination therapy with non-selective COX inhibitors to prevent COX-related gastric injuries |
| US8658160B1 (en) | 2006-10-17 | 2014-02-25 | Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center | Composition and method for cancer chemoprevention |
| US20080171085A1 (en) * | 2007-01-11 | 2008-07-17 | Natrol, Inc. | Novel biphasic delivery system for a pharmaceutical or nutraceutical composition and method of administration |
| WO2008100249A1 (en) * | 2007-02-13 | 2008-08-21 | Kos Life Sciences, Inc. | Low flush niacin formulation |
| WO2009067684A1 (en) * | 2007-11-21 | 2009-05-28 | Capricorn Pharma Inc. | Modified release niacin formulations |
| KR20110011643A (en) * | 2008-06-02 | 2011-02-08 | 닥터 레디스 레보러터리즈 리미티드 | Modified release niacin formulations |
| WO2009149056A2 (en) * | 2008-06-02 | 2009-12-10 | Dr. Reddy's Laboratories Ltd. | Combinations of niacin and an oxicam |
| RU2657797C2 (en) | 2012-06-15 | 2018-06-15 | Конарис Рисерч Инститьют Аг | Pharmaceutical composition containing nicotinic acid and/or nicotinamide and/or tryptophan for positively influencing the intestinal microbiota |
| US10758552B2 (en) | 2013-12-13 | 2020-09-01 | Conaris Research Institute Ag | Pharmaceutical composition containing combinations of nicotinamide and 5-aminosalicylic acid for beneficially influencing the intestinal microbiota and/or treating gastrointestinal inflammation |
| EP3079675B1 (en) * | 2013-12-13 | 2020-02-12 | CONARIS research institute AG | A pharmaceutical composition containing nicotinic acid and/or nicotinamide for use in beneficially influencing blood lipid levels by modifying the intestinal microbiota |
Family Cites Families (249)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US32581A (en) * | 1861-06-18 | Mortimer kelson | ||
| US29652A (en) * | 1860-08-14 | maltby | ||
| US2510164A (en) * | 1945-04-24 | 1950-06-06 | Us Agriculture | Water-insoluble derivatives of nicotinic acid and process for preparing them |
| US2540979A (en) * | 1948-04-24 | 1951-02-06 | Smith Kline French Lab | Enteric coating |
| US2749274A (en) * | 1952-05-06 | 1956-06-05 | Bristol Lab Inc | Stable aqueous procaine penicillin suspension |
| US2798837A (en) * | 1952-11-20 | 1957-07-09 | Sahyun Melville | Achlorhydria composition |
| US2851453A (en) * | 1954-08-09 | 1958-09-09 | Smith Kline French Lab | Cellulose derivative product, compositions comprising the same and their preparation |
| US2798838A (en) * | 1954-11-10 | 1957-07-09 | Smith Kline French Lab | Method of preparing acetophenetidin tablets |
| US2805977A (en) * | 1955-01-04 | 1957-09-10 | Smith Kline French Lab | Sustained release pharmaceutical preparation |
| US2857313A (en) * | 1956-03-27 | 1958-10-21 | Ciba Pharm Prod Inc | Self-lubricating granulation |
| US3065143A (en) * | 1960-04-19 | 1962-11-20 | Richardson Merrell Inc | Sustained release tablet |
| DE1228029C2 (en) * | 1964-05-09 | 1973-05-17 | Merck Ag E | Process for the production of tablets by pressing powder mixtures without prior granulation |
| US3930017A (en) * | 1965-10-07 | 1975-12-30 | Horst Kummer | Lowering blood cholesterol and lipid levels |
| US3849554A (en) * | 1965-12-01 | 1974-11-19 | Nasa | Reduction of blood serum cholesterol |
| US3862332A (en) * | 1967-05-11 | 1975-01-21 | Dow Chemical Co | Method of lowering serum cholesterol |
| US3639636A (en) * | 1967-06-01 | 1972-02-01 | Dow Chemical Co | Method of lowering serum cholesterol |
| US3626071A (en) * | 1968-03-08 | 1971-12-07 | Richardson Merrell Inc | Compositions and methods for reducing cholesterol in the blood |
| US3495011A (en) * | 1968-10-28 | 1970-02-10 | Unimed Inc | Reduction of blood level cholesterol |
| US3634584A (en) * | 1969-02-13 | 1972-01-11 | American Home Prod | Sustained action dosage form |
| US3590117A (en) * | 1969-03-24 | 1971-06-29 | Richardson Merrell Inc | Long-lasting troche containing guar gum |
| US3629393A (en) * | 1969-09-11 | 1971-12-21 | Nikken Chemicals Co Ltd | Release-sustaining-tablet |
| US3870790A (en) * | 1970-01-22 | 1975-03-11 | Forest Laboratories | Solid pharmaceutical formulations containing hydroxypropyl methyl cellulose |
| US3721735A (en) * | 1970-07-15 | 1973-03-20 | C Thiffault | Compositions for and method of lowering cholesterol levels |
| US3806601A (en) * | 1970-11-18 | 1974-04-23 | Egyt Gyogyszervegyeszeti Gyar | Cholesterol- and lipoid-lowering therapeutical agent |
| US3709991A (en) * | 1970-11-23 | 1973-01-09 | Hoffmann La Roche | Hypolipidemic method |
| GB1338235A (en) * | 1970-12-15 | 1973-11-21 | May & Baker Ltd | Azapurinones |
| US3859437A (en) * | 1972-06-02 | 1975-01-07 | Intellectual Property Dev Corp | Reducing cholesterol levels |
| US3795691A (en) * | 1971-06-23 | 1974-03-05 | American Home Prod | Cholesterol-lowering agents |
| US3773920A (en) * | 1971-07-14 | 1973-11-20 | Nikken Chemicals Co Ltd | Sustained release medicinal composition |
| US3923972A (en) * | 1971-10-12 | 1975-12-02 | Monsanto Co | Method of lowering blood cholesterol level |
| US4237118A (en) * | 1972-03-06 | 1980-12-02 | Howard Alan N | Dietary supplement and dietary methods employing said supplement for the treatment of obesity |
| US3951821A (en) * | 1972-07-14 | 1976-04-20 | The Dow Chemical Company | Disintegrating agent for tablets |
| JPS4954572A (en) * | 1972-09-29 | 1974-05-27 | ||
| US3992536A (en) * | 1972-11-11 | 1976-11-16 | Boehringer Ingelheim Gmbh | Pharmaceutical compositions containing a 1-phenyl-2,2,4,4-C1 -C2 alkyl-3-[4-phenyl of pyridyl)-piperazino]-cyclobutanol-(1) and method of use |
| US3959492A (en) * | 1972-12-08 | 1976-05-25 | Istituto Chemioterapico Italiano | Method for reducing serum blood cholesterol |
| US4180064A (en) * | 1972-12-27 | 1979-12-25 | Alza Corporation | System for delivering agent to environment of use over prolonged time |
| US4034087A (en) * | 1973-12-17 | 1977-07-05 | The Regents Of The University Of Michigan | Pharmaceutical composition and process of treatment |
| US4115550A (en) * | 1973-04-23 | 1978-09-19 | Monsanto Company | Composition for lowering blood cholesterol level |
| US3868416A (en) * | 1973-10-01 | 1975-02-25 | American Cyanamid Co | Hypolipidemic 4-(monoalkylamino)benzoic acid derivatives |
| DE2363511A1 (en) * | 1973-12-20 | 1975-07-10 | Bayer Ag | PYRAZOLE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT |
| US4182902A (en) * | 1973-12-27 | 1980-01-08 | Siegfried Aktiengesellschaft | Novel cholesterol-lowering compounds |
| US3864416A (en) * | 1974-03-18 | 1975-02-04 | Universal Oil Prod Co | Separation of tetra-alkyl substituted aromatic hydrocarbon isomers |
| US3965255A (en) * | 1974-05-01 | 1976-06-22 | E. E. Eljim Ecology Ltd. | Controlled drug releasing preparations |
| US4014987A (en) * | 1974-06-04 | 1977-03-29 | Alza Corporation | Device for delivery of useful agent |
| US4166902A (en) * | 1974-10-14 | 1979-09-04 | Paolo Ferruti | High polymers containing nicotinic acid, process for their preparation and their use |
| IT1044798B (en) * | 1974-10-15 | 1980-04-21 | Ferruti Paolo | HIGH POLYMERS CONTAINING NICOTINIC ACID PROCESS FOR THEIR PREPARATION AND USE |
| US4011339A (en) * | 1975-08-15 | 1977-03-08 | Sandoz, Inc. | Hypolipidemic allene carboxylic acids |
| JPS5231981A (en) * | 1975-08-18 | 1977-03-10 | Takeda Chem Ind Ltd | Microcapsule preparation method |
| US3977404A (en) * | 1975-09-08 | 1976-08-31 | Alza Corporation | Osmotic device having microporous reservoir |
| US4034758A (en) * | 1975-09-08 | 1977-07-12 | Alza Corporation | Osmotic therapeutic system for administering medicament |
| US4077407A (en) * | 1975-11-24 | 1978-03-07 | Alza Corporation | Osmotic devices having composite walls |
| US4058122A (en) * | 1976-02-02 | 1977-11-15 | Alza Corporation | Osmotic system with laminated wall formed of different materials |
| US4014334A (en) * | 1976-02-02 | 1977-03-29 | Alza Corporation | Laminated osmotic system for dispensing beneficial agent |
| US4008719A (en) * | 1976-02-02 | 1977-02-22 | Alza Corporation | Osmotic system having laminar arrangement for programming delivery of active agent |
| US4126672A (en) * | 1976-02-04 | 1978-11-21 | Hoffmann-La Roche Inc. | Sustained release pharmaceutical capsules |
| US4140755A (en) * | 1976-02-13 | 1979-02-20 | Hoffmann-La Roche Inc. | Sustained release tablet formulations |
| US4167558A (en) * | 1976-02-13 | 1979-09-11 | Hoffmann-La Roche Inc. | Novel sustained release tablet formulations |
| US4178387A (en) * | 1976-03-30 | 1979-12-11 | William H. Rorer, Inc. | Method for the treatment of arrhythmia |
| US4203439A (en) * | 1976-11-22 | 1980-05-20 | Alza Corporation | Osmotic system with volume amplifier for increasing amount of agent delivered therefrom |
| US4160452A (en) * | 1977-04-07 | 1979-07-10 | Alza Corporation | Osmotic system having laminated wall comprising semipermeable lamina and microporous lamina |
| US4256108A (en) * | 1977-04-07 | 1981-03-17 | Alza Corporation | Microporous-semipermeable laminated osmotic system |
| US4169944A (en) * | 1977-09-19 | 1979-10-02 | University Patents, Inc. | Cholesterol biosynthesis inhibitors |
| US4348399A (en) * | 1978-02-02 | 1982-09-07 | American Cyanamid Company | Antiatherosclerotic and hypolipidemic 4-(monoalkylamino)phenyl alkane, alkene and alkyne carbinols, aldehydes, carboxylic acids and derivatives |
| US4283382A (en) * | 1977-12-28 | 1981-08-11 | Eastman Kodak Company | Fluorescent labels comprising rare earth chelates |
| US4211783A (en) * | 1978-03-20 | 1980-07-08 | American Cyanamid Company | Hypolipidemic and antiatherosclerotic novel 4-(aralkyl- and heteroarylalkylamino)phenyl compounds |
| US4230878A (en) * | 1978-03-08 | 1980-10-28 | American Cyanamid Company | Hypolipidemic and antiatherosclerotic 4-[(cyclopropyl alkyl)amino]benzoic acids and derivatives |
| US4205085A (en) * | 1978-03-09 | 1980-05-27 | American Cyanamid Company | Hypolipidemic and antiatherosclerotic 4-(polyfluoroalkylamino)phenyl compounds |
| DE2903579A1 (en) * | 1978-02-03 | 1979-08-09 | Sigma Tau Ind Farmaceuti | USE OF ACETYL CARNITINE AND OTHER ACYLDER DERIVATIVES OF CARNITINE FOR THE TREATMENT OF HYPERLIPOPROTEINEMIC AND HYPERLIMPIDAEMIA AND MEDICINAL PRODUCTS |
| DE2903558C2 (en) * | 1978-02-03 | 1994-09-01 | Sigma Tau Ind Farmaceuti | Use of L-carnitine |
| US4318914A (en) * | 1978-03-09 | 1982-03-09 | American Cyanamid Company | Hypolipidemic and antiatherosclerotic 4-(polyfluoro-alkylamino)phenyl compounds |
| US4305959A (en) * | 1978-03-09 | 1981-12-15 | American Cyanamid Company | Hypolipidemic and antiatherosclerotic 4-(polyfluoro-alkylamino)phenyl compounds |
| US4310545A (en) * | 1978-03-09 | 1982-01-12 | American Cyanamid Company | Hypolipidemic and antiatherosclerotic 4-(polyfluoroalkylamino) phenyl compounds |
| DD146547A5 (en) * | 1978-07-15 | 1981-02-18 | Boehringer Sohn Ingelheim | MEDICINAL RETARDANT SHAPE WITH UNFORGETTABLE POROESEN DIFFUSION SHELLS |
| DE2965855D1 (en) | 1978-09-25 | 1983-08-18 | Farlane Stuart John Mc | Pharmaceutical preparations containing a mollusc extract |
| US4485105A (en) | 1978-10-12 | 1984-11-27 | American Cyanamid Company | Method of treating hyperlipidemia with 4-(monoalkylamino)benzoic acid amides |
| US4321268A (en) | 1979-02-08 | 1982-03-23 | Merz & Co. | Certain substituted phenyl esters of nicotinic acid, compositions and methods of using same |
| DE2905979C2 (en) * | 1979-02-16 | 1981-01-22 | Carl-Jacob Gatzen | Use of acetylated, distilled monoglycerides for the treatment of lipid metabolic disorders in humans |
| JPS55153715A (en) * | 1979-05-18 | 1980-11-29 | Nikken Kagaku Kk | Prolonged granule of theophylline |
| US4226849A (en) * | 1979-06-14 | 1980-10-07 | Forest Laboratories Inc. | Sustained release therapeutic compositions |
| US4357469A (en) * | 1979-06-14 | 1982-11-02 | Forest Laboratories, Inc. | Carrier base material for prolonged release therapeutic compositions |
| US4382143A (en) * | 1979-07-23 | 1983-05-03 | American Cyanamid Company | Hypolipidemic and antiatherosclerotic novel (monosubstituted-amino)heteroaryl carboxylic acids and analogs |
| US4251519A (en) * | 1979-07-30 | 1981-02-17 | Anheuser-Busch, Incorporated | Process for the prevention and reduction of elevated blood cholesterol and triglycerides levels |
| US4248857A (en) * | 1979-08-09 | 1981-02-03 | American Home Products Corporation | Sustained release pharmaceutical compositions |
| US4309404A (en) * | 1979-08-09 | 1982-01-05 | American Home Products Corporation | Sustained release pharmaceutical compositions |
| US4353887A (en) * | 1979-08-16 | 1982-10-12 | Ciba-Geigy Corporation | Divisible tablet having controlled and delayed release of the active substance |
| US4568547A (en) | 1979-08-30 | 1986-02-04 | Herschler R J | Solid pharmaceutical compositions comprising MSM and their production |
| US4285951A (en) * | 1979-09-07 | 1981-08-25 | Warner-Lambert Company | 2,2-Dimethyl-5-(2,5-dimethylphenoxy)pentyl ester of 3-pyridine carboxylic acid and use as an anti-atherosclerotic agent |
| US4440940A (en) * | 1979-10-17 | 1984-04-03 | American Cyanamid Company | Anti-atherosclerotic agents |
| US4259314A (en) * | 1979-12-10 | 1981-03-31 | Hans Lowey | Method and composition for the preparation of controlled long-acting pharmaceuticals |
| US4308251A (en) * | 1980-01-11 | 1981-12-29 | Boots Pharmaceuticals, Inc. | Controlled release formulations of orally-active medicaments |
| DE3000979A1 (en) * | 1980-01-12 | 1981-07-23 | Dr. Karl Thomae Gmbh, 7950 Biberach | NEW DIPYRIDAMOL RETARD FORMS AND METHOD FOR THEIR PRODUCTION |
| US4279898A (en) * | 1980-04-22 | 1981-07-21 | Research Foundation Of The City University Of New York | In vivo inhibitors of cholesterol biosynthesis |
| US4282233B1 (en) * | 1980-06-19 | 2000-09-05 | Schering Corp | Antihistaminic 11-(4-piperidylidene)-5h-benzoÄ5,6Ü-cyclohepta-Ä1,2Ü-pyridines |
| US4362711A (en) * | 1980-07-11 | 1982-12-07 | Evreka Inc. | Blood cholesterol level reducing agent and method |
| US4291030A (en) * | 1980-07-25 | 1981-09-22 | Unimed, Inc. | Method of lowering blood cholesterol |
| US4326525A (en) * | 1980-10-14 | 1982-04-27 | Alza Corporation | Osmotic device that improves delivery properties of agent in situ |
| US4465660A (en) | 1981-04-01 | 1984-08-14 | Mead Johnson & Company | Sustained release tablet containing at least 95 percent theophylline |
| US4375468A (en) * | 1981-07-13 | 1983-03-01 | Verex Laboratories, Inc. | Constant order release aspirin composition and method of treating arthritis |
| JPS5839618A (en) | 1981-09-04 | 1983-03-08 | Chugai Pharmaceut Co Ltd | Long-acting laminated tablet |
| US4369172A (en) * | 1981-12-18 | 1983-01-18 | Forest Laboratories Inc. | Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose |
| US4525345A (en) | 1981-12-24 | 1985-06-25 | Verex Laboratories, Inc. | Constant order release, solid dosage indomethacin formulation and method of treating arthritis and other inflammatory conditions |
| US4389393A (en) * | 1982-03-26 | 1983-06-21 | Forest Laboratories, Inc. | Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose |
| US4428951A (en) * | 1982-04-22 | 1984-01-31 | Fujisawa Pharmaceutical Co., Ltd. | Long acting pharmaceutical composition |
| FR2525474A1 (en) | 1982-04-26 | 1983-10-28 | Roussel Uclaf | NEW ORAL PHARMACEUTICAL FORM OF CLOMETACIN |
| US4556678A (en) | 1982-06-24 | 1985-12-03 | Key Pharmaceuticals, Inc. | Sustained release propranolol tablet |
| US4457907A (en) | 1982-08-05 | 1984-07-03 | Clear Lake Development Group | Composition and method for protecting a therapeutic drug |
| US4452775A (en) * | 1982-12-03 | 1984-06-05 | Syntex (U.S.A.) Inc. | Cholesterol matrix delivery system for sustained release of macromolecules |
| US4472436A (en) | 1982-12-06 | 1984-09-18 | Neo-Bionics, Inc. | Increasing HDL-cholesterol levels with phenylethylamine derivatives |
| US4522804A (en) | 1983-01-03 | 1985-06-11 | Verex Laboratories, Inc. | Constant release rate solid oral dosage formulations of propranolol |
| US4461759A (en) | 1983-01-03 | 1984-07-24 | Verex Laboratories, Inc. | Constant release rate solid oral dosage formulations of veropamil |
| JPS59155309A (en) | 1983-02-22 | 1984-09-04 | Teijin Ltd | Active type vitamin d3 composition and its preparation |
| US4673405A (en) | 1983-03-04 | 1987-06-16 | Alza Corporation | Osmotic system with instant drug availability |
| US4576604A (en) | 1983-03-04 | 1986-03-18 | Alza Corporation | Osmotic system with instant drug availability |
| DE3435325A1 (en) | 1983-04-09 | 1986-04-17 | Nikken Chemicals Co., Ltd., Tokio/Tokyo | LONG-TERM THEOPHYLLIN TABLET AND METHOD FOR THE PRODUCTION THEREOF |
| DE3314003A1 (en) | 1983-04-18 | 1984-10-18 | Boehringer Ingelheim KG, 6507 Ingelheim | DIVISIBLE TABLET WITH DELAYED ACTIVE SUBSTANCE RELEASE AND METHOD FOR THE PRODUCTION THEREOF |
| DE3315877A1 (en) | 1983-05-02 | 1984-11-08 | Merz + Co GmbH & Co, 6000 Frankfurt | N-OXIDES OF PYRIDYL CARBONIC ACID ESTERS, A METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THESE COMPOUNDS |
| US4882167A (en) | 1983-05-31 | 1989-11-21 | Jang Choong Gook | Dry direct compression compositions for controlled release dosage forms |
| US4571333A (en) | 1983-06-14 | 1986-02-18 | Syntex (U.S.A.) Inc. | Controlled release naproxen and naproxen sodium tablets |
| US4539198A (en) | 1983-07-07 | 1985-09-03 | Rowell Laboratories, Inc. | Solid pharmaceutical formulations for slow, zero order release via controlled surface erosion: expanded range |
| US4690824A (en) | 1983-07-07 | 1987-09-01 | Redi-Rowell, Inc. | Solid pharmaceutical formulations for slow, zero order release via controlled surface erosion: expanded range |
| US4684516A (en) | 1983-08-01 | 1987-08-04 | Alra Laboratories, Inc. | Sustained release tablets and method of making same |
| JPS6035385A (en) | 1983-08-03 | 1985-02-23 | Hitachi Maxell Ltd | Disk cartridge |
| DE3469343D1 (en) | 1983-08-19 | 1988-03-24 | Nissan Chemical Ind Ltd | Antiatherosclerotic agent |
| US4749575A (en) | 1983-10-03 | 1988-06-07 | Bio-Dar Ltd. | Microencapsulated medicament in sweet matrix |
| US4605666A (en) | 1983-10-24 | 1986-08-12 | Basf Corporation | Process for preparing spray-dried powders containing a water-soluble vitamin and powders prepared thereby |
| US4680323A (en) | 1983-12-01 | 1987-07-14 | Hans Lowey | Method and composition for the preparation of controlled long-acting pharmaceuticals for oral administration |
| US4795327A (en) | 1984-03-26 | 1989-01-03 | Forest Laboratories, Inc. | Controlled release solid drug dosage forms based on mixtures of water soluble nonionic cellulose ethers and anionic surfactants |
| US4849229A (en) | 1984-03-26 | 1989-07-18 | Forest Laboratories, Inc. | Controlled release solid drug dosage forms based on mixtures of water soluble nonionic cellulose ethers and anionic surfactants |
| US4540566A (en) | 1984-04-02 | 1985-09-10 | Forest Laboratories, Inc. | Prolonged release drug dosage forms based on modified low viscosity grade hydroxypropylmethylcellulose |
| JPS60209523A (en) | 1984-04-03 | 1985-10-22 | Mitsubishi Petrochem Co Ltd | Antilipemic agent |
| US4963367A (en) | 1984-04-27 | 1990-10-16 | Medaphore, Inc. | Drug delivery compositions and methods |
| US4603142A (en) | 1984-06-01 | 1986-07-29 | Wisconsin Alumni Research Foundation | Cholesterol lowering method of use |
| US4713245A (en) | 1984-06-04 | 1987-12-15 | Mitsui Toatsu Chemicals, Incorporated | Granule containing physiologically-active substance, method for preparing same and use thereof |
| JPS6124516A (en) | 1984-07-12 | 1986-02-03 | Fujisawa Pharmaceut Co Ltd | Long active tablet |
| US4610870A (en) | 1984-10-05 | 1986-09-09 | E. R. Squibb & Sons, Inc. | Controlled release formulation |
| US4678516A (en) | 1984-10-09 | 1987-07-07 | The Dow Chemical Company | Sustained release dosage form based on highly plasticized cellulose ether gels |
| IE58110B1 (en) | 1984-10-30 | 1993-07-14 | Elan Corp Plc | Controlled release powder and process for its preparation |
| US4747881A (en) | 1985-02-05 | 1988-05-31 | Warner-Lambert Company | Ingestible aggregate and delivery system prepared therefrom |
| FR2578423B1 (en) | 1985-03-06 | 1988-12-30 | Grimberg Georges | GUAR GUM-BASED PHARMACEUTICAL COMPOSITION FOR THE PROTECTION OF THE OESO-GASTRO-DUODENAL MUCOSA |
| US4657757A (en) | 1985-03-29 | 1987-04-14 | Schering Corporation | Controlled release dosage form comprising acetaminophen, pseudoephedrine sulfate and dexbrompheniramine maleate |
| US4695591A (en) | 1985-03-29 | 1987-09-22 | Schering Corporation | Controlled release dosage forms comprising hydroxypropylmethylcellulose |
| CA1279574C (en) | 1985-04-17 | 1991-01-29 | Jeffrey L. Finnan | Process for lubricating water-soluble vitamin powders |
| EP0207638B1 (en) | 1985-06-04 | 1990-12-19 | Teijin Limited | Sustained-release pharmaceutical preparation |
| FR2585246A1 (en) | 1985-07-26 | 1987-01-30 | Cortial | PROCESS FOR OBTAINING SOLID PHARMACEUTICAL FORMS WITH PROLONGED RELEASE |
| GB8521494D0 (en) | 1985-08-29 | 1985-10-02 | Zyma Sa | Controlled release tablet |
| US4710519A (en) | 1985-09-30 | 1987-12-01 | Basf Corporation | Process for preparing spray dried acetaminophen powder and the powder prepared thereby |
| CA1259915A (en) | 1985-10-09 | 1989-09-26 | Sailen S. Mookerjea | Means to reduce plasma cholesterol |
| IT1187750B (en) | 1985-10-15 | 1987-12-23 | Eurand Spa | PROCEDURE FOR THE PREPARATION OF TABLETS, EVEN OF PROLONGED RELEASE, OF ISCSORBIDE-5-MONONITRATE STABILIZED AND FORMULATIONS SO OBTAINED |
| US4753801A (en) | 1985-10-25 | 1988-06-28 | Eli Lilly And Company | Sustained release tablets |
| US4734285A (en) | 1985-10-28 | 1988-03-29 | The Dow Chemical Company | Sustained release compositions |
| JPS62106019A (en) | 1985-11-01 | 1987-05-16 | Terumo Corp | Anti-hyperlipemic agent |
| US4704285A (en) | 1985-11-18 | 1987-11-03 | The Dow Chemical Company | Sustained release compositions comprising hydroxypropyl cellulose ethers |
| DE3541428A1 (en) | 1985-11-23 | 1987-05-27 | Hoechst Ag | NEW BASICALLY SUBSTITUTED PYRIDINE COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF, THE MEDICINAL PRODUCTS CONTAINING IT AND THEIR USE |
| US4696762A (en) | 1985-12-06 | 1987-09-29 | Zumbro Enterprises, Inc. | Hydroxypropylmethylcellulose |
| IT1188212B (en) | 1985-12-20 | 1988-01-07 | Paolo Colombo | SYSTEM FOR THE RELEASE SPEED OF ACTIVE SUBSTANCES |
| IE63321B1 (en) | 1986-02-03 | 1995-04-05 | Elan Corp Plc | Drug delivery system |
| US4837032A (en) | 1986-02-04 | 1989-06-06 | Farval Ag | Theophylline sustained release tablet |
| IT1191674B (en) | 1986-03-07 | 1988-03-23 | Eurand Spa | FORMULATIONS FOR THE PREPARATION OF PROLONGED-RELEASE DRUGS SUITABLE FOR ORAL ADMINISTRATION |
| US4775535A (en) | 1986-04-04 | 1988-10-04 | Hans Lowey | Method of preparing controlled long-acting pharmaceutical formulations in unit dosage form having uniform and comparable bioavailability characteristics |
| US4855143A (en) | 1986-04-04 | 1989-08-08 | Hans Lowey | Method of preparing controlled long-acting pharmaceutical formulations in unit dosage form having uniform and comparable bioavailability characteristics |
| SE8601624D0 (en) | 1986-04-11 | 1986-04-11 | Haessle Ab | NEW PHARMACEUTICAL PREPARATIONS |
| US4756911A (en) | 1986-04-16 | 1988-07-12 | E. R. Squibb & Sons, Inc. | Controlled release formulation |
| DE3614019A1 (en) | 1986-04-25 | 1987-11-05 | Degussa | METHOD FOR PRODUCING HIGH PURITY CRYSTAL CRYSTALLINE NICOTINIC ACID |
| US4795642A (en) | 1986-05-01 | 1989-01-03 | Pharmacaps, Inc. | Gelatin-encapsulated controlled-release composition |
| US4708834A (en) | 1986-05-01 | 1987-11-24 | Pharmacaps, Inc. | Preparation of gelatin-encapsulated controlled release composition |
| US4752479A (en) | 1986-05-27 | 1988-06-21 | Ciba-Geigy Corporaton | Multi vitamin and mineral dietary supplement with controlled release bioavailable iron |
| GB8613689D0 (en) | 1986-06-05 | 1986-07-09 | Euro Celtique Sa | Pharmaceutical composition |
| GB8613688D0 (en) | 1986-06-05 | 1986-07-09 | Euro Celtique Sa | Pharmaceutical composition |
| US4946870A (en) | 1986-06-06 | 1990-08-07 | Union Carbide Chemicals And Plastics Company Inc. | Delivery systems for pharmaceutical or therapeutic actives |
| US4824672A (en) | 1986-06-06 | 1989-04-25 | Hauser-Kuhrts, Inc. | Method and composition for reducing serum cholesterol |
| IT1200178B (en) | 1986-07-23 | 1989-01-05 | Alfa Farmaceutici Spa | GALENIC FORMULATIONS WITH SCHEDULED SALE CONTAINING DRUGS WITH ANTI-FLOGISTIC ACTIVITY |
| CH668187A5 (en) | 1986-08-07 | 1988-12-15 | Ciba Geigy Ag | THERAPEUTIC SYSTEM WITH SYSTEMIC EFFECT. |
| US4814354A (en) | 1986-09-26 | 1989-03-21 | Warner-Lambert Company | Lipid regulating agents |
| US4851233A (en) | 1986-10-06 | 1989-07-25 | Warner-Lambert Company | Sustained release formulations |
| GB8628359D0 (en) | 1986-11-27 | 1986-12-31 | Zyma Sa | Galenical formulation |
| US4824677A (en) | 1986-12-18 | 1989-04-25 | The Unjohn Company | Grooved tablet for fractional dosing of sustained release medication |
| ATE72111T1 (en) | 1987-01-14 | 1992-02-15 | Ciba Geigy Ag | THERAPEUTIC SYSTEM FOR POORLY SOLUBLE ACTIVE INGREDIENTS. |
| US4744907A (en) | 1987-01-16 | 1988-05-17 | Interferon Sciences, Inc. | Blood cell separation |
| JP2547995B2 (en) | 1987-01-26 | 1996-10-30 | 昭和電工株式会社 | Granules for ruminants and method for producing the same |
| US5015479A (en) | 1987-02-02 | 1991-05-14 | Seamus Mulligan | Sustained release capsule or tablet formulation comprising a pharmaceutically acceptable dihydropyridine |
| US4851232A (en) | 1987-02-13 | 1989-07-25 | Alza Corporation | Drug delivery system with means for obtaining desirable in vivo release rate pattern |
| US4968508A (en) | 1987-02-27 | 1990-11-06 | Eli Lilly And Company | Sustained release matrix |
| US4915952A (en) | 1987-02-27 | 1990-04-10 | Alza Corporation | Composition comprising drug, HPC, HPMC and PEO |
| US4789549A (en) | 1987-03-09 | 1988-12-06 | Warner-Lambert Company | Sustained release dosage forms |
| US4786503A (en) | 1987-04-06 | 1988-11-22 | Alza Corporation | Dosage form comprising parallel lamine |
| KR960011236B1 (en) | 1987-05-08 | 1996-08-21 | 스미스 클라인 앤드 프렌취 라보라토리스 리미티드 | Pharmaceutical compositions of cimetidine |
| GB8710965D0 (en) | 1987-05-08 | 1987-06-10 | Smith Kline French Lab | Pharmaceutical compositions |
| JPS63310827A (en) * | 1987-06-15 | 1988-12-19 | Sanwa Kagaku Kenkyusho Co Ltd | Sustained release pharmaceutical containing nicotinic aid derivative as principal agent |
| DE3720757A1 (en) | 1987-06-24 | 1989-01-05 | Bayer Ag | DHP COAT TABLET |
| US4759923A (en) | 1987-06-25 | 1988-07-26 | Hercules Incorporated | Process for lowering serum cholesterol using poly(diallylmethylamine) derivatives |
| DE3721721C1 (en) | 1987-07-01 | 1988-06-09 | Hoechst Ag | Process for coating granules |
| FR2618073B1 (en) | 1987-07-16 | 1990-09-07 | Pf Medicament | HYDROPHILIC MATRIX-TYPE TABLETS BASED ON SALBUTAMOL AND THEIR PREPARATION METHOD |
| US4792452A (en) | 1987-07-28 | 1988-12-20 | E. R. Squibb & Sons, Inc. | Controlled release formulation |
| US4795644A (en) | 1987-08-03 | 1989-01-03 | Merck & Co., Inc. | Device for pH independent release of drugs through the Donnan-like influence of charged insoluble resins |
| US4814183A (en) | 1987-08-31 | 1989-03-21 | Merck & Co., Inc. | Device for the controlled release of drugs with Donnan-like modulation by charged insoluble resins |
| US4994276A (en) | 1988-09-19 | 1991-02-19 | Edward Mendell Co., Inc. | Directly compressible sustained release excipient |
| IL87710A (en) | 1987-09-18 | 1992-06-21 | Ciba Geigy Ag | Covered floating retard form for controlled release in gastric juice |
| IE60311B1 (en) | 1987-09-24 | 1994-06-29 | American Home Prod | Sustained release etodolac |
| SE8703881D0 (en) | 1987-10-08 | 1987-10-08 | Haessle Ab | NEW PHARMACEUTICAL PREPARATION |
| EP0513874B1 (en) | 1987-10-09 | 1996-07-10 | KOTOBUKI & CO., LTD. | Writing tool |
| US5023245A (en) | 1987-11-10 | 1991-06-11 | Hauser-Kuhrts, Inc. | Improved niacin formulation |
| US4965252A (en) | 1988-06-28 | 1990-10-23 | Hauser-Kuhrts, Inc. | Cholesterol-lowering combination compositions of guar gum and niacin |
| US4911917A (en) | 1988-06-28 | 1990-03-27 | Hauser-Kuhrts, Inc. | Cholesterol-lowering combination comopsitions of magnesium salt and niacin |
| US4946963A (en) | 1987-11-13 | 1990-08-07 | The University Of North Carolina At Chapel Hill | Compounds for the control of hyperlipidemia using N-substituted isoxazolidine-3,5-diones |
| US5211958A (en) | 1987-11-30 | 1993-05-18 | Gist-Brocades, N.V. | Pharmaceutical composition and process for its preparation |
| US4983398A (en) | 1987-12-21 | 1991-01-08 | Forest Laboratories, Inc. | Sustained release drug dosage forms containing hydroxypropylmethylcellulose and alkali metal carboxylates |
| US5178854A (en) | 1988-03-24 | 1993-01-12 | Taisho Pharmaceutical Co., Ltd. | Cholesterol-lowering agents |
| DE3812402A1 (en) | 1988-04-14 | 1989-10-26 | Basf Ag | METHOD FOR THE PRODUCTION OF WATER-SOLUBLE COPOLYMERISATS BASED ON MONOETHYLENICALLY UNSATURATED CARBONIC ACIDS AND THE USE THEREOF |
| US5096714A (en) | 1988-06-28 | 1992-03-17 | Hauser-Kuhrts, Inc. | Prolonged release drug tablet formulations |
| US4866058A (en) | 1988-07-27 | 1989-09-12 | Izydore Robert A | Method for control of hyperlipidemia |
| US5034528A (en) | 1988-07-27 | 1991-07-23 | North Carolina Central University | Compositions for the control of hyperlipidemia |
| US5196440A (en) | 1988-07-29 | 1993-03-23 | Zambon Group S.P.A. | Compounds active as inhibitors of the cholesterol biosynthesis |
| US5169639A (en) | 1988-09-19 | 1992-12-08 | Edward Mendell Co., Inc. | Controlled release verapamil tablets |
| US4999380A (en) | 1988-10-18 | 1991-03-12 | Nestec S.A. | Treatment of lipoprotein disorders associated with cholesterol metabolism |
| US4920123A (en) | 1988-10-21 | 1990-04-24 | Beyer Jr Karl H | Method for controlling and/or lowering serum triglyceride and/or cholesterol levels in mammals |
| US5110817A (en) | 1988-10-21 | 1992-05-05 | Beyer Jr Karl H | Method for controlling and/or lowering serum triglyceride and/or cholesterol levels in mammals |
| US4997658A (en) | 1988-11-21 | 1991-03-05 | Merck & Co., Inc. | Method for enhancing the lowering of plasma cholesterol levels |
| US5260305A (en) | 1988-12-12 | 1993-11-09 | E. R. Squibb & Sons, Inc. | Combination of pravastatin and nicotinic acid or related acid and method for lowering serum cholesterol using such combination |
| US5039341A (en) | 1988-12-19 | 1991-08-13 | The Dow Chemical Company | Binder composition comprises a blend of a high viscosity and low viscosity hydroxypropyl methylcellulose ether, and a tape joint composition containing such binder |
| US4920115A (en) | 1988-12-28 | 1990-04-24 | Virginia Commonwealth University | Method of lowering LDL cholesterol in blood |
| US4970081A (en) | 1989-01-03 | 1990-11-13 | Sterling Drug Inc. | Controlled-release, low-dose aspirin formulation and method of treating vascular occlusive disease therewith |
| US5032406A (en) | 1989-02-21 | 1991-07-16 | Norwich Eaton Pharmaceuticals, Inc. | Dual-action tablet |
| JP2664238B2 (en) | 1989-03-01 | 1997-10-15 | 日清製粉株式会社 | Nicotinic acid or its ester derivatives |
| US5268181A (en) | 1989-04-13 | 1993-12-07 | Upsher-Smith Laboratories, Inc. | Method of using niacin to control nocturnal cholesterol synthesis |
| US5126145A (en) | 1989-04-13 | 1992-06-30 | Upsher Smith Laboratories Inc | Controlled release tablet containing water soluble medicament |
| US4990535A (en) | 1989-05-03 | 1991-02-05 | Schering Corporation | Pharmaceutical composition comprising loratadine, ibuprofen and pseudoephedrine |
| US5133974A (en) | 1989-05-05 | 1992-07-28 | Kv Pharmaceutical Company | Extended release pharmaceutical formulations |
| US5264226A (en) | 1989-07-12 | 1993-11-23 | Roquette Freres | Process for preparing dairy products with a low content of sterols, particularly of cholesterol |
| US5262165A (en) | 1992-02-04 | 1993-11-16 | Schering Corporation | Transdermal nitroglycerin patch with penetration enhancers |
| DK469989D0 (en) | 1989-09-22 | 1989-09-22 | Bukh Meditec | PHARMACEUTICAL PREPARATION |
| US5171570A (en) | 1989-12-08 | 1992-12-15 | Lotte Company Limited | Substance having suppressing function for diseases relating to increase in cholesterol, and foods and drinks in which it is used |
| US5009895A (en) | 1990-02-02 | 1991-04-23 | Merck & Co., Inc. | Sustained release with high and low viscosity HPMC |
| US5190940A (en) | 1990-09-14 | 1993-03-02 | American Home Products Corporation | Cholesterol ester hydrolase inhibitors |
| US5130333A (en) | 1990-10-19 | 1992-07-14 | E. R. Squibb & Sons, Inc. | Method for treating type II diabetes employing a cholesterol lowering drug |
| US5190970A (en) | 1990-10-19 | 1993-03-02 | E. R. Squibb & Sons, Inc. | Method for preventing onset of or treating Type II diabetes employing a cholesterol lowering drug alone or in combination with an ace inhibitor |
| US5286736A (en) | 1990-11-22 | 1994-02-15 | Dr. Karl Thomae Gmbh | Pyridyl compounds and pharmaceutical compositions containing these compounds |
| GB9100437D0 (en) | 1991-01-09 | 1991-02-20 | Glaxo Group Ltd | Chemical compounds |
| US5145678A (en) | 1991-01-22 | 1992-09-08 | Dusko Gakic | Method of reducing blood serum cholesterol |
| US5182298A (en) | 1991-03-18 | 1993-01-26 | Merck & Co., Inc. | Cholesterol lowering agents |
| US5256689A (en) | 1991-05-10 | 1993-10-26 | Merck & Co., Inc. | Cholesterol lowering compounds |
| US5169638A (en) | 1991-10-23 | 1992-12-08 | E. R. Squibb & Sons, Inc. | Buoyant controlled release powder formulation |
| US5262435A (en) | 1992-02-10 | 1993-11-16 | Merck & Co., Inc. | Cholesterol lowering compounds |
| US5167964A (en) | 1992-02-14 | 1992-12-01 | Warner-Lambert Company | Semi-enteric drug delivery systems and methods for preparing same |
| US5258401A (en) | 1992-07-10 | 1993-11-02 | Merck & Co., Inc. | Cholesterol lowering compounds |
| US5314697A (en) | 1992-10-23 | 1994-05-24 | Schering Corporation | Stable extended release oral dosage composition comprising loratadine and pseudoephedrine |
| US6080428A (en) * | 1993-09-20 | 2000-06-27 | Bova; David J. | Nicotinic acid compositions for treating hyperlipidemia and related methods therefor |
| EP2319513A1 (en) * | 1993-09-20 | 2011-05-11 | Abbott Respiratory LLC | Nicotinic acid compositons for treating hyperlipidemia and related methods therefor |
| US6129930A (en) * | 1993-09-20 | 2000-10-10 | Bova; David J. | Methods and sustained release nicotinic acid compositions for treating hyperlipidemia at night |
| AU5787996A (en) * | 1995-04-19 | 1996-11-07 | Lipoprotein Technologies, Inc. | Compositions, kits, and methods for administration of antilipemic and anti-platelet aggregation drugs |
-
1997
- 1997-03-06 US US08/814,974 patent/US6129930A/en not_active Expired - Lifetime
-
1998
- 1998-03-06 AU AU63481/98A patent/AU6348198A/en not_active Abandoned
- 1998-03-06 AT AT98910260T patent/ATE289197T1/en not_active IP Right Cessation
- 1998-03-06 DE DE69829042T patent/DE69829042T2/en not_active Expired - Lifetime
- 1998-03-06 CA CA002283322A patent/CA2283322C/en not_active Expired - Lifetime
- 1998-03-06 EP EP98910260A patent/EP0966284B1/en not_active Expired - Lifetime
- 1998-03-06 BR BR9815457-5A patent/BR9815457A/en not_active Application Discontinuation
- 1998-03-06 WO PCT/US1998/004590 patent/WO1998039002A1/en active Application Filing
- 1998-03-06 CA CA002591710A patent/CA2591710A1/en not_active Abandoned
- 1998-03-06 EP EP98907745A patent/EP0969837A1/en not_active Ceased
- 1998-03-06 ES ES98910260T patent/ES2234100T3/en not_active Expired - Lifetime
- 1998-03-06 BR BR9815454-0A patent/BR9815454A/en not_active Application Discontinuation
- 1998-03-06 AU AU64545/98A patent/AU6454598A/en not_active Abandoned
- 1998-03-06 CA CA002283159A patent/CA2283159C/en not_active Expired - Lifetime
- 1998-03-06 WO PCT/US1998/004578 patent/WO1998039001A1/en active IP Right Grant
-
1999
- 1999-09-02 NO NO994275A patent/NO994275L/en not_active Application Discontinuation
- 1999-09-02 NO NO994248A patent/NO994248L/en not_active Application Discontinuation
- 1999-09-06 FI FI991895A patent/FI119910B/en not_active IP Right Cessation
- 1999-09-06 FI FI991896A patent/FI19991896A/en not_active Application Discontinuation
- 1999-12-22 US US09/470,603 patent/US7011848B1/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2283159A1 (en) | 1998-09-11 |
| FI19991895A (en) | 1999-09-22 |
| NO994275D0 (en) | 1999-09-02 |
| BR9815454A (en) | 2001-10-23 |
| AU6454598A (en) | 1998-09-22 |
| DE69829042T2 (en) | 2006-05-04 |
| EP0966284B1 (en) | 2005-02-16 |
| NO994275L (en) | 1999-10-11 |
| EP0966284A1 (en) | 1999-12-29 |
| BR9815457A (en) | 2001-10-16 |
| NO994248D0 (en) | 1999-09-02 |
| WO1998039002A1 (en) | 1998-09-11 |
| WO1998039001A1 (en) | 1998-09-11 |
| CA2283322A1 (en) | 1998-09-11 |
| NO994248L (en) | 1999-10-20 |
| US6129930A (en) | 2000-10-10 |
| AU6348198A (en) | 1998-09-22 |
| EP0969837A1 (en) | 2000-01-12 |
| ES2234100T3 (en) | 2005-06-16 |
| ATE289197T1 (en) | 2005-03-15 |
| FI119910B (en) | 2009-05-15 |
| CA2283159C (en) | 2007-06-19 |
| FI19991896A (en) | 1999-09-22 |
| DE69829042D1 (en) | 2005-03-24 |
| US7011848B1 (en) | 2006-03-14 |
| CA2591710A1 (en) | 1998-09-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2283322C (en) | Starter kit containing nicotinic acid compositions | |
| US20070225342A1 (en) | Nicotinic Acid Compositions For Treating Hyperlipidemia and Related Methods Therefor | |
| US20080300284A1 (en) | Nicotinic acid compositions for treating hyperlipidemia and related methods therefor | |
| US6818229B1 (en) | Intermediate release nicotinic acid compositions for treating hyperlipidemia | |
| US6746691B2 (en) | Intermediate release nicotinic acid compositions for treating hyperlipidemia having unique biopharmaceutical characteristics | |
| US20130005779A1 (en) | Methods for treating hyperlipidemia with intermediate release nicotinic acid compositions having unique biopharmaceutical characteristics | |
| US20030157153A1 (en) | Intermediate release nicotinic acid compositions for treating hyperlipidemia having unique biopharmaceutical characteristics | |
| US20110301207A1 (en) | Methods and sustained release nicotinic acid compositions for treating hyperlipidemia | |
| AU775967B2 (en) | Starter kit containing nicotinic acid compositions | |
| CA2574987A1 (en) | Nicotinic acid compositions for treating hyperlipidemia and related methods therefor | |
| AU4751702A (en) | Nicotinic acid compositions for treating hyperlipidemia and related methods therefor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDC | Discontinued application reinstated | ||
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20180306 |
|
| MKEX | Expiry |
Effective date: 20180306 |