|Número de publicación||US3870790 A|
|Tipo de publicación||Concesión|
|Fecha de publicación||11 Mar 1975|
|Fecha de presentación||25 Oct 1972|
|Fecha de prioridad||22 Ene 1970|
|Número de publicación||US 3870790 A, US 3870790A, US-A-3870790, US3870790 A, US3870790A|
|Inventores||Lowey Hans, Stafford Herbert Henry|
|Cesionario original||Forest Laboratories|
|Exportar cita||BiBTeX, EndNote, RefMan|
|Citas de patentes (5), Citada por (243), Clasificaciones (8)|
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet|
United States Patent [191 Lowey et al.
[ Mar. 11, 1975 SOLID PHARMACEUTICAL FORMULATIONS CONTAINING HYDROXYPROPYL METHYL CELLULOSE  Inventors: Hans Lowey, Mamaroneck; Herbert Henry Stafford, Staten lsland, both of N.Y.
 Assignee: Forest Laboratories, Inc., New
 Filed: Oct. 25, 1972  Appl. No.: 300,745
Related U.S. Application Data  Continuation-in-part of Ser. No. 5,140, Jan. 22, 1970, abandoned, which is a continuation-in-part of Ser. No. 626.968, March 30, 1967, abandoned.
 References Cited UNITED STATES PATENTS 2,887,440 5/1959 Grcminger et a1 424/362 X 2,949,401 8/1960 Wershaw 424/362 X 3,181,998 5/1965 Kanig Cyr ct a1. Nurnbcrg 424/238 X Primary Examiner-Albert T. Meyers Assistant E.raminer-Leonard Schenkman  ABSTRACT A solid pharmaceutical composition in which the carrier consists essentially of hydroxypropylmethylcellulose, or hydroxypropylmethylcellulose admixed with up to about 20% ethylcellulose, is prepared by compressing a mixture comprising one therapeutic agent and the hydroxypropylmethylcellulose powder which has been humidified to a moisture content of from about 5 to about 25% by weight at a low compression pressure. The solid pharmaceutical composition obtained will release the active ingredient contained therein evenly over a prolonged period, e.g. from about 1 to 8 hours.
3 Claims, No Drawings SOLID PHARMACEUTICAL FORMULATIONS CONTAINING HYDROXYPROPYL METHYL CELLULOSE CROSS-REFERENCE This is a continuation-in-part of U.S. application Ser. No. 5,140, filed Jan. 22, 1970 now abandoned, which, in turn, is a continuation-in-part of U.S. application Ser. No. 626,968, filed Mar. 30, 1967, now abandoned.
DETAILED DESCRIPTION Sustained release products of conventional character are well known to the art and have been found to have a number of advantages. Specifically, the release of the medication contained therein is uniform and continuous over a period of time, thereby avoiding the necessity of frequent administration of the medicament while at the same time achieving a desired blood level of active ingredient. The preparation of sustained release compositions often requires a rather substantial and complicated procedure and often the degree ofpredictability and the release pattern are less than optimum.
The use of cellulose derivatives such as hydroxypropylmethylcellulose as an ingredient in pharmacetical formulations is of course known. Thus U.S. Pat. No. 3,266,992 describes the incorporation of up to 30% of various cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose and hydroxyethylcellulose, the particular derivative depending upon the nature of the therapeutic agent, into tablets to effect rapid disintegration thereof. U.S. Pat. No. 2,887,440 on the other hand discloses the use of hydroxypropylmethylcellulose in enteric coatings to prevent disintegration of the tablet core. It has also been recognized that methylcellulose might itself be a desirable material for certain pharmaceutical formulations but attempts at achieving such products have not met with success. Thus U.S. Pat. No. 2,949,401 recognizes the desirable properties of methylcellulose in a buccal tablet containing vitamin A but limits the amount to from 3 to 5%. Trotter and coworkers report several unsuccessful attempts at directly compressing methylcellulose into a troche and succeeded only by incorporating 25% superfine sugar with the methylcellulose. Amer. Jour. Pharm, February 1956, pp. 5056. The combination of cellulose derivatives with large amounts of lactose is also described in U.S. Pat. No. 3,344,030. U.S. Pat. No. 3,590,117 reports the unsatisfactory nature of hydroxypropylmethylcellulose for troches. U.S. Pat. No. 3,312,594 describes troches containing carboxymethylcellulose but only in combination with equal amounts of pectin and gelatin.
The present invention relates to a long-acting sustained dosage unit, and the carriers and active ingredients in the composition thereof, presented in a solid coherent form. The long-acting dosage unit contains at least one active ingredient compressed with a mixture containing a moisturized carrier consisting esentially of 100 to 80% by weight of hydroxypropylmethylcellulose and optionally 0 to 20% by weight of ethylcellulose. The carrier ingredient during use gradually releases the active ingredient by contact with fluids, such as saliva, gastric juices, and other natural secretions and does so over an extended period, e.g., about 1 to 8 hours. In one aspect the invention comprises a long-acting troche, lozenge or tablet. The solid pharmaceutical form according to the present invention can however be utilized in other routes of administration in addition to buccal. Thus the solid form may be administered orally as a tablet to be swallowed or rectally or vaginally as a suppository.
Specifically, the carrier is hydroxypropylmethylcellulose which has been humidified under controlled conditions to a moisture content of from about 5 to about 25% by weight. This material, optionally containing ethylcellulose, can then be compressed at a low pressure, e.g. only 5 to 8 pounds per square inch, which, because of the moisture content, is sufficient to shape the material into a solid coherent pharmaceutical form such as a troche to be sucked or used in the oral cavity so as to effect a gradual release of the active therapeutic ingredient which is absorbed through the oral mucosa through the blood stream. Higher degrees of compression, e.g., up to about pounds per square inch, yield a harder and more long lasting composition as might be desired for example in a suppository to be inserted in the rectum or vagina, or a tablet to be simply swallowed.
According to the present invention it has now been found that a reliable and effective long acting sustained action solid dosage unit can be very simply made by compressing an appropriate amount of practically any desired active ingredient or medicament with a premoisturized hydroxypropylmethylcellulose powder or with a mixture of a combination of moisturized hydroxypropylmethylcellulose and ethylcellulose powder. The release time, the dosage unit and pattern of release can be controlled by the relative amounts of hydroxypropylmethylcellulose and ethylcellulose employed, the size and weight of the tablet product, the degree of compression or a combination thereof, bearing in mind that a high degree of moisturization permits the use of low compression pressures, and visa versa, for the blend of active ingredient and cellulose powder and that increased compression increases the compositions span of action. It is thus an important feature of the present invention that a sustained release product can be readily and easily prepared containing, as the sole carrier, varying amounts of hydroxypropylmethylcellulose and ethylcellulose having a predetermined moisture content and that by controlled variation of the moisture content of the alkylated cellulose carrier pow der, the duration of the release period of the active medicament held in the compacted tablet may be controlled. The release of the active ingredient is, therefore, controlled by the size and the weight, moisture content and degree of compression pressure exercised on the lozenge, suppository or tablet at the time it is being formed from the pre-wetted powder and active medicament.
In general, the long acting carrier products of the present invention are produced by combining the appropriate amount of active ingredient into the shape of troches, lozenges, tablets or suppositories with a mixture of from about -80% by weight of hydroxypropylmethylcellulose and from about 020% by weight of ethylcellulose. The product can also contain adjuvants such as a synthetic sweetening agent as for example saccharin, a nontoxic food grade color such as FD&C Yellow No. 10, a flavoring agent such as cherry flavor and a preservative such as pmethylbenzoic acid. The only criterion for the addition of such materials is that they do not tend to dehydrate the product before or after it is tableted by compression techniques.
Specific techniques for the manufacture and use of the long acting carrier will be set forth in greater detail below but an illustration of the improved activity of the product may briefly be noted by the following illustration. For example, a grain lozenge when held in the mouth will release its active ingredient in a regular manner over a period of one and one-and-one-half hours by dissolution or disintegration of the lozenge by the saliva fluids. If the same lozenge is inserted in the upper cavity of the mouth, the release then can be extended to 3 hours. Moreover a shaped product or tablet of the present invention which has a weight of about grains is noted to take almost twice as long to release its active ingredient as a 5 grain product.
When used as a lozenge, release through the action of the saliva is continuous and the active ingredient then passes through the gastro-intestinal tract into the blood stream. However, when the composition is positioned in the buccal pouch, absorption of the active ingredient takes place through the mucosa membrane lining the pouch directly through the capillaries in the blood stream.
A similar pattern can be observed when the solid pharamaceutical form takes the form of a suppository. Here again the exclusive carrier has highly desirable properties in that it is non-irritating, substantially neutral and adherent.
While the solid pharmaceutical forms of the present invention intended for oral administration; i.e., tablets to be swallowed, will be subjected to the effects of both gastric and intestinal fluids and mechanical wear within the gastrointestinal tract, a prolonged rate of release is also seen here.
The invention has flexibility and versatility dependent upon the particular nature of the active ingredient which is to be dispensed, the treatment or condition for which the active ingredient is indicated, the route of administration and the desired length of release time of the active ingredient. It has been found that one may for example prepare a 50 lb. mixture for the production of long acting troches from a composition indicated in the following Table:
TABLE No. Make of Materials Lbs. Ozs. Grs.
l 0.10% Calcium cyclamate 350 2 [00% Cherry Flavor 8 3 0.10% Methyl Paraben 350 4 0.01% Propyl Paraben 35 5 0.50% Lake Dye.Red No. 2 4 6 Mixture of 85% Methocel HG 6O 49 2 140 (20% of H 0), premium viscosity 50 and l5% Ethylcellulose N50 tions are not only permissible but are intended as these variations affect the release time and pattern of the active ingredient.
In preparing troches from the above mixture, items 1, 2, 3 and 4 are weighed out and thoroughly mixed. Item 5, which is the food grade dye, is placed in a mortar and rubbed with some of the mixture of Items 1, 2, 3 and 4 following which the remainder of Items 1, 2, 3 and 4 is added and the rubbing is conducted until a homogenous blend is obtained. Item 6, which is the specifled cellulose powder mixture, is added to the previously produced mixtures of Items 1, 2, 3, 4 and 5 and the entire composition is blended until uniformity is achieved. The uniform dry mixture of ingredients is then spread out on trays and thoroughly sprayed with a 35% mixture of ethanol and distilled water. The thus treated mixture is allowed to dry overnight and is then ground on a Fitzpatrick mill to an average 2040 mesh particle size. The powder derived from the Fitzpatrick mill is next placed on trays which trays are put into a steam room and held there overnight under conditions of very high humidity for the express purpose of creating in the previously dry blend, certain moisture levels which are important in the ultimate performance of each tablet in simultaneously maintaining its integrity and sustained even release of active ingredient. As a means of maintaining the desired humidity at a fixed level in the powder, trays filled with water are placed in the steam room to maintain the even consistency of the humidity level to insure adequate wetting of the powder. The room temperature is about F and humidity is maintained between about 78 to 82% for 24 hours (overnight). The resulting material will have a moisture content from about 20 to about 25% by weight.
After a constant moisture level is thus achieved, the active ingredient is added and the entire batch of material is placed in the hopper of a conventional tableting machine which is set up with half-inch punches and dies and the machine is adjusted and regulated for 8 pounds of pressure per square inch and for product size. In this manner, 7 /2 grain or 10 grain tablets preferably, are produced and by following the same procedure, but suitably further adjusting the machine, 12 grain or other size tablets are produced.
Alternatively, the procedure is carried out by introducing the hydroxypropylmethylcellulose or a mixture of the hydroxypropylmethylcellulose with ethylcellulose into an oven chamber having an exhaust aperture whichis at that time in closed or shut position. The chamber is provided with a heating unit and a forced air blower, which is inoperative at this stage of the procedure, the heat and forced air being applied at a subsequent stage. The material to be processed is placed in thin layers (not more than inch thick) on trays of the oven chamber which are lined with heat-resistant parchment paper and the trays are placed on racks in the oven chamber using only alternate shelves, thereby providing a predetermined amount of spacing between the layers of material being treated. There is then placed within the oven chamber a humidifier equipped with a humidistat which is pre-set to maintain humidity in the oven chamber at 85 the humidifier being filled with sufficient distilled or deionized water to last for 24 to 36 hours. The humidifier is now activated and the oven chamber is closed and the process is allowed to proceed under the 85 90% humidity for a minimum of 24 hours. Humidification can be continued for up to 36 hours or even longer if desired, although there is no special advantage in exceeding 36 hours and unduly extended times are apt to be uneconomical, but the treatment should be continued at least about 24 hours. The humidifier is then removed from the oven chamber, the exhaust aperture opened by manipulation of the valve and the forced air blower is activated thereby applying heat at a controlled temperature in the range of 100 to 120F (43 to 49C). The moisture content will then decrease, depending upon the length of time the mate rial is treated with the hot air. At the end of 12 hours for example the moisture content of the treated material is at its lowest limit of the range, about 5%. This is not an exact limit since this added moisture content can be as low as 4 or 4 6%, as determined by a standard moisture determination apparatus. The 12-hour period just referred to is also approximate as the duration of the period may vary somewhat above or below 12 hours, but it has been found in practice that the period should not exceed approximately 12 hours.
When the required added moisture content is achieved, the treated material is removed from the oven and passed through a No. 2 stainless steel screen employing a Fitzpatrick mill and processed as described above.
Variations in the two extremes are of course readily apparent, the critical factor being that the hydroxypropylmethylcellulose is so treated that its moisture content is stabilized at a higher level than is normally encountered.
The hydroxypropylmethylcellulose preferably employed is identified as Methocel HG 60 which is a commercial methylcellulose product manufactured by the Dow Chemical Company, Midland, Michigan and has a methoxyl percentage of 28 to 30%, a hydroxypropoxyl percentage of 7 to 12%, is soluble in water and organic solvents, has a normal gel temperature of 60F and demonstrates an average viscosity of 50 centipoises (range 40 to 60, 2% aqueous solution).
As regards the ethylcellulose, this material corresponds to that defined in the National Formulary XIII with a standard ethoxy content ranging between 44.0 and 51.0%, preferably 4849..5%, by weight. The preferred material corresponds to ethylcellulose N50, the number N50 indicating the viscosity in centipoises of a 5% by weight solution of the product in a 80/20 toluene/ethanol solvent at a temperature of 25C. These viscosity numbers are indicative of the size of the ethylcellulose molecules, the larger the molecule, the greater the viscosity and can be further referred to in the standard charts on the products which are readily available.
The active ingredient may be of any suitable nature such as insulin, vitamins, hormones, analgesics, local anesthetics, epinephrine, antiinflammatory steroids, progestational agents, antibiotics, antiseptics, antimycotics, antacids and the like. The nature of the therapeutic agent is not critical and any drug, or stable combination of drugs, can be incorporated into these novel pharmaceutical forms. This is particularly important since some active medicaments such as insulin, antidiuretic hormones and epinephrine become inactivated when incorporated into conventional or previously known sustained release products where the products are swallowed and the release occurs in the gastric fluids or in the intestinal fluids or in a combination of both. Some active agents such as ACTH, epinephrine, vitamin B iron insulin, antidiuretic hormones, prednisolone and nitroglycerine as well as antiobesity agents and antacids can, in accordance with the present invention, be administered via the transmucosal absorption route. However those therapuetic agents which are active when swallowed, can also be administered in the new pharmaceutical carrier of the present invention, the composition being used exactly like a conventional tablet. Similarly, antimicrobial agents such as furazolidone and nifuroxime can be administered in a vaginal suppository. Products of the present invention are also useful as demulcents in the treatment of painful ulcerations, inflammations, and irritations. These effects have been shown by in vitro and in vivo clinical tests.
Moreover, it can be shown by X-ray studies a tablet prepared according to the present invention for very long release, while gradually dissolving remains coherent for most of its passage through the gastro-intestinal tract. Hence a tablet of the moisturized hydroxypropylmethylcellulose and barium sulfate (as an X-ray contrast agent) having a total weight of 600 mg, a diameter of 12.7 mm, a thickness of 3.15 mm and a hardness of 6.6 lbs/in can still be seen in X-rays for more than 5 hours after administration. A typical progression is as follows:
1 hr. small intestine 1 hr. 35 min. do.
2 hr. 20 min. do.
5 hr. 10 min. caecum Since the therapeutic agent is being continuously released, the observed period of activity will be even longer than this.
The invention is further illustrated by the following non-limitative examples:
EXAMPLES l-ll SUSTAINED RELEASE TROCHE FORMULATIONS 50 LB. MIXTURE FOR 50,000 TABLETS AT 7 GRAINS EXAMPLE 1 PREDNISOLONE, 4 MG.
No. Make of Materials Lbs. Ozs. Grs.
l. Prednisolone 7 60 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 6O 48 l l hydroxypropylmethylcellulose,
premium, viscosity 50,
moisture 20% by weight EXAMPLE 2 EPINEPHRINE, 1 MG No. Make of Materials Lbs. Ozs. Grs.
l. Epinephrine l 330 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 49 245 EXAMPLE 2-C0ntinued EXAMPLE 7 EPIN EPHRINE, 1 MG No. Make of Materials Lbs. Ozs. Grs.
hydroxypropylmethylcellulose, premium,viscosity O moisture 20% by weight EXAMPLE 3 DIBUCAINE, 3 MG No. Make of Materials 1 L Ozs. Grs.
1. Dibucaine 5 I50 2. 0.10% Calcium cyclamate 350 3. 100% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 48 12 440 hydroxypropylmethylcellulose premium,viscosity 5O moisture 20% by weight EXAMPLE 4 BENZOCAINE, 20 MG No. Make of Materials Lbs. Ozs. Grs.
1. Benzocaine 2 3 300 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 46 14 290 hydroxypropylmethylcellulose premium, viscosity 50 moisture 20% by weight EXAMPLE 5 TRIAMCINOLONE ACETONIDE, 0.25 MG No. Make of Materials Lbs. Ozs. Grs
1. Triamcinolone Acetonide 188 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 49 1 402 hydroxypropylmethylcellulose premium, viscosity 50 moisture 20% by weight EXAMPLE 6 HEPARIN, 50 MG No. Make of Materials Lbs. Ozs. Grs.
1. Heparin 5 8 165 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 6O 35 5 210 hydroxypropylmethylcellulose premium, viscosity 50, moisture 20% by weight 8. Ethocel N50 ethylcellulose 9 2 70 VITAMIN B12, 1000 MCG No. Make of Materials Lbs. 07s. Grs.
1. Vitamin B 1 330 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 41 10 hydroxypropylmethylcelluose premium, viscosity 50 moisture 20% by weight 8. Ethocel N50 ethylcellulose 8 3 345 EXAMPLE 8 INSULIN, 250 INT. UNITS No. Make of Materials Lbs. Ozs. Grs.
l. Insulin 1 330 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 3S 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 hydroxypropylmethylcellulose, premium, viscosity 50 moisture 20% by weight EXAMPLE 9 SODIUM BICARBONATE, 0.3 GM GRAIN TABLETS No. Make of Materials Lbs. Ozs. Grs.
1. Sodium Bicarbonate 33 1 23 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 53 hydroxypropylmethylcellulose premium, viscosity 5O moisture 20% by weight 8. Ethocel N50 ethylcellulose 13 14 412 EXAMPLE l0 d-DESOXYEPHEDRINE HYDROCHLORIDE, 5 MG No. Make of Materials Lbs. Ozs. Grs.
1. d-Desoxyephedrine Hydrochloride 8 390 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 49 7 45 hydroxypropylmethylcellulose, premium, viscosity 50 moisture 20% by weight In examples 1 10, the calcium cyclamate can be replaced by 0.1 the amount of sodium saccharin while the Lake Dye Red No. 2 can be replaced by another pharmaceutically acceptable coloring agent or omitted altogether from the formulation.
EXAMPLE ll REPRESENTATIVE RELEASE PATTERNS 260 individual tests have been made on 31 subjects with both lozenges and tablets inserted either in the buccal pouch on held sublingually, and show the following results:
LOZENGES Partial dissolution time Medium range per 1/10 gram carrier, 15.8 to 21.5 minutes. Medium range per 7 grain lozenge, 81 to 108 minutes. Medium range per 14 grain tablet, 158 to 215 minutes.
2. Total dissolution time.
3. Total dissolution time.
TABLETS INSERTED IN BUCCAL POUCH OR USED SUBLINGUALLY 1. Partial dissolution time. Medium range per 1/10 gram carrier, 29.4 to 42.1 minutes. Medium range per 7 grain tablet, 149 to 212 minutes. Medium range per 14 grain tablet, 294 to 421 minutes.
2. Total dissolution time.
3. Total dissolution time.
EXAMPLE 12 Analgesic Tablet Ingredients mg/tablet 1 Aspirin powder U.S.P. 525.0 2 Methocel HG 60 hydroxypropylmethylcellulose,
premium, viscosity 50, moisture 5% by weight 325.5 3. Glycine 45.0 4. Syloid 244 micron size silica 4.5
Ingredients 1, 2 and 3 are mixed in a bowl into which ingredient 4 is added after screening and the whole blended for 20 minutes and compressed in a tableting machine having a one-half inch die size and a one-half inch punch to make tablets with an average weight of 0.9 g and a thickness of 0.210 t 0.01 inch. The hardness of the tablet was 2228.6 lbs/square inch.
EXAMPLE l3 Antihistamine Tablet Ingredients mg/tablet l Chlorpheniramine maleate U.S.P. 12.60 2 Methocel HG 60 509.20
hydroxypropylmethylcellulose, premium. viscosity 50, moisture 4%% bylweight 3 Methyl paraben .S.P 0.52 4 Propyl faraben U.S.P. 0.06 5 Syloid 44 micron size silica 2.63
Ingredient 2 was placed in a container and ingredients l. 3, 4 and 5 were weighed out and added after screening and the whole blended for 20 minutes. The compression into tablets was conducted on a tableting machine using a die size of seven-sixteenths inch with a pound of seven-sixteenths inch to obtain a. tablet thickness of 0.250 t 0.01 inch with a tablet hardness of 2228.6 lbs/square inch. Each tablet weighed 0.525
3, 4 and 5 and the whole blended for 20 minutes and compressed as in Example 13. The tablet thickness was 0.250 $0.01 inch and the hardness was 22.2 lbs/square inch. Each tablet weighed 0.55 g.
EXAMPLE 15 Laxative Tablet Ingredients mg/tablet 1 Phenolphthalein U.S.P. 66.0 2 Methocel HG 60 480.64
premium, viscosity 50,
moisture 4% by weight 3 Methyl paraben U.S.P. 0.55 4 Propylgaraben U.S.P. 0.06 5 Syloid 44 2.75
The same procedure was followed as in Example 13 with the same results.
EXAMPLE 16 Vitamin Tablet Ingredients mg/tahlet Ascorbic acid, U.S.P., powder Methocel HG 60 hydroxypropylmethylcellulose, premium, viscosity 50, moisture 5% by weight 3 Syloid 244 g 4 Ingredients 1 and 2 were weighed out as in the preceding examples and placed into a stainless steel bowl into which ingredient 3 was added after screening and the whole blended for 20 minutes and compressed as previously described. The tablets had a thickness of 0.210 t 0.01 inch and a hardness of 22.2-28.6 lbs/square inch. Each tablet weighed 0.8 g.
EXAMPLE 17 Ingredients Amount/Suppository l Furazolidone 0.005 g 2 Nifuroxime 0.007 g 3 Methocel HG 60 1.988 g hydroxypropylmethylcellulose,
premium, viscosity 5 moisture 7.5% by weight The ingredients are thoroughly mixed and compressed in a similar fashion to that described above utilizing however a suppository mold to yield a vaginal suppository weighing 2 g.
The above ingredients are mixed and thoroughly blended for minutes and then compressed to for rectal suppositories of 1.14 g each.
What is claimed is:
l. A method of preparing a long-acting compressed buccal composition for the administration of transmucosally absorbed therapeutic agents consisting essentially of the therapeutic agent and a carrier which comprises subjecting an effective amount of a dry carrier consisting of from to of hydroxypropyl methyl cellulose having a methoxyl content of 28 to 30% and a hydroxypropyl content of 7 to 12% and from 20 to 0% of ethyl cellulose having an ethoxy content of 48 to 49.5% to controlled humidity for a time sufficient to establish a moisture content of from about 5 to about 25%, mixing the moisturized carrier with a therapeutically effective amount of the therapeutic agent and compressing the mixture into solid shaped units at a pressure of from about 5 to about 8 pounds per square inch.
2. The product prepared by the process of claim 1.
3. The product of claim 1 which additionally contains a synthetic sweetening agent, a coloring agent, a flavoring agent and a preservative.
UNITED STATES PATENT AND TRADEMARK OFFICE @ETTTTQATE PATENT NO. 3 870,,790 DATED Mamh 9 1975 iN\/ ENTOR(S) Hans Lowey 5: Herbert Henry Stafford It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
In Examples 6 7 and 9, the last line of each should read N50 Ethyleellulose by deleting "Ethocel".
' win. me we ismei a eom e. mm c. mesmu: ANN
Anminfi QT/RW v Commissioner oj'Parems and Trademarks
|Patente citada||Fecha de presentación||Fecha de publicación||Solicitante||Título|
|US2887440 *||12 Ago 1957||19 May 1959||Dow Chemical Co||Enteric coating|
|US2949401 *||28 Jul 1958||16 Ago 1960||Dome Chemicals Inc||Buccal tablet containing vitamin a|
|US3181998 *||12 Ago 1960||4 May 1965||Kanig Joseph L||Tablet disintegration|
|US3312594 *||21 Jun 1963||4 Abr 1967||Squibb & Sons Inc||Longlasting troche|
|US3424842 *||4 May 1965||28 Ene 1969||Merck Ag E||Manufacture of tablets directly from dry powders|
|Patente citante||Fecha de presentación||Fecha de publicación||Solicitante||Título|
|US3976764 *||11 Mar 1975||24 Ago 1976||Eisai Co., Ltd.||Solid therapeutic preparation remaining in stomach|
|US4163777 *||29 Abr 1977||7 Ago 1979||Lewis/Howe Company||Controlled antacid delivery form and method of treatment therewith|
|US4183898 *||25 May 1978||15 Ene 1980||Liff Lawrence J||Liquid base makeup composition|
|US4188188 *||27 Sep 1978||12 Feb 1980||Bio-Rad Laboratories, Inc.||High density lipoprotein cholesterol assay|
|US4226849 *||14 Jun 1979||7 Oct 1980||Forest Laboratories Inc.||Sustained release therapeutic compositions|
|US4259314 *||10 Dic 1979||31 Mar 1981||Hans Lowey||Method and composition for the preparation of controlled long-acting pharmaceuticals|
|US4292300 *||20 Jul 1977||29 Sep 1981||Inveresk Research International||Controlled release suppositories|
|US4349535 *||11 Ene 1980||14 Sep 1982||Liff Lawrence J||Liquid base makeup composition|
|US4357469 *||29 Jun 1981||2 Nov 1982||Forest Laboratories, Inc.||Carrier base material for prolonged release therapeutic compositions|
|US4369172 *||18 Dic 1981||18 Ene 1983||Forest Laboratories Inc.||Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose|
|US4389393 *||26 Mar 1982||21 Jun 1983||Forest Laboratories, Inc.||Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose|
|US4432975 *||19 Oct 1981||21 Feb 1984||Icn Pharmaceuticals, Inc.||Process for introducing vitamin B-12 into the bloodstream|
|US4465660 *||21 Dic 1982||14 Ago 1984||Mead Johnson & Company||Sustained release tablet containing at least 95 percent theophylline|
|US4529589 *||29 Sep 1983||16 Jul 1985||Davydov Anatoly B||Pharmaceutical composition for the treatment of diabetes mellitus|
|US4540566 *||2 Abr 1984||10 Sep 1985||Forest Laboratories, Inc.||Prolonged release drug dosage forms based on modified low viscosity grade hydroxypropylmethylcellulose|
|US4547358 *||4 Jun 1984||15 Oct 1985||Mead Johnson & Company||Sustained release tablet containing at least 95 percent theophylline|
|US4647599 *||9 Nov 1984||3 Mar 1987||Egyt Gyogyszervegyeszeti Cyar||Sustained release pharmaceutical tablets and process for the preparation thereof|
|US4668517 *||4 Abr 1985||26 May 1987||Norwich Eaton Pharmaceuticals, Inc.||Furazolidone dosage form|
|US4680323 *||1 Dic 1983||14 Jul 1987||Hans Lowey||Method and composition for the preparation of controlled long-acting pharmaceuticals for oral administration|
|US4695591 *||22 Nov 1985||22 Sep 1987||Schering Corporation||Controlled release dosage forms comprising hydroxypropylmethylcellulose|
|US4713239 *||19 Nov 1985||15 Dic 1987||Vsesojuny Kardiologichesky Nauchny Tsentr Adkaemii Meditsinski Nauk Sssr||Antianginal film and method of treating ischemic heart disease|
|US4764378 *||10 Feb 1986||16 Ago 1988||Zetachron, Inc.||Buccal drug dosage form|
|US4775535 *||4 Abr 1986||4 Oct 1988||Hans Lowey||Method of preparing controlled long-acting pharmaceutical formulations in unit dosage form having uniform and comparable bioavailability characteristics|
|US4786503 *||6 Abr 1987||22 Nov 1988||Alza Corporation||Dosage form comprising parallel lamine|
|US4803079 *||20 Dic 1985||7 Feb 1989||Syntex (U.S.A.) Inc.||Controlled release naproxen and naproxen sodium tablets|
|US4842854 *||13 May 1987||27 Jun 1989||Vsesojuzny Kardiologichesky Nauchny Tsentr Akademii Meditsinskiki Nauk Ssr||Antianginal plate for treating ischemic heart disease|
|US4851232 *||8 Jun 1987||25 Jul 1989||Alza Corporation||Drug delivery system with means for obtaining desirable in vivo release rate pattern|
|US4855143 *||12 Jul 1988||8 Ago 1989||Hans Lowey||Method of preparing controlled long-acting pharmaceutical formulations in unit dosage form having uniform and comparable bioavailability characteristics|
|US4880830 *||9 Feb 1987||14 Nov 1989||Ethical Pharmaceuticals Limited||Slow release formulation|
|US4921695 *||9 Mar 1989||1 May 1990||Babaian Eduard A||Antianginal plate for treating ischemic heart disease|
|US4942040 *||29 Sep 1988||17 Jul 1990||Aktiebolaget Hassle||Pharmaceutical preparation and a process for its preparation|
|US4946685 *||1 Sep 1988||7 Ago 1990||Alza Corporation||Cellulosic dosage form|
|US4950484 *||2 Mar 1988||21 Ago 1990||Gist-Brocades N.V.||Pharmaceutical tablet, pharmaceutical granulate and process for their preparation|
|US4983398 *||15 Dic 1988||8 Ene 1991||Forest Laboratories, Inc.||Sustained release drug dosage forms containing hydroxypropylmethylcellulose and alkali metal carboxylates|
|US5028633 *||21 Feb 1985||2 Jul 1991||Freund Industrial Co., Ltd.||Excipient for use in compression molding and process of preparation|
|US5126145 *||11 Jun 1990||30 Jun 1992||Upsher Smith Laboratories Inc||Controlled release tablet containing water soluble medicament|
|US5204116 *||1 May 1991||20 Abr 1993||Alza Corporation||Dosage form providing immediate therapy followed by prolonged therapy|
|US5268181 *||29 Jun 1992||7 Dic 1993||Upsher-Smith Laboratories, Inc.||Method of using niacin to control nocturnal cholesterol synthesis|
|US5292518 *||16 Mar 1992||8 Mar 1994||Hauser-Kuhrts||Prolonged-release drug tablet formulations|
|US5338550 *||21 Dic 1992||16 Ago 1994||Alza Corporation||Stereoisomer therapy|
|US5393765 *||13 Dic 1993||28 Feb 1995||Hoffmann-La Roche Inc.||Pharmaceutical compositions with constant erosion volume for zero order controlled release|
|US5403593 *||31 Mar 1992||4 Abr 1995||Sandoz Ltd.||Melt granulated compositions for preparing sustained release dosage forms|
|US5436009 *||15 Dic 1992||25 Jul 1995||Dagra Pharma B.V.||Sustained release suppositories and a process for preparation|
|US5472712 *||23 Jun 1993||5 Dic 1995||Euroceltique, S.A.||Controlled-release formulations coated with aqueous dispersions of ethylcellulose|
|US5478572 *||6 Sep 1994||26 Dic 1995||Bristol-Myers Squibb Co.||Gepirone dosage form|
|US5484607 *||13 Oct 1993||16 Ene 1996||Horacek; H. Joseph||Extended release clonidine formulation|
|US5672360 *||22 Nov 1994||30 Sep 1997||Purdue Pharma, L.P.||Method of treating pain by administering 24 hour oral opioid formulations|
|US5681585 *||20 Jun 1996||28 Oct 1997||Euro-Celtique, S.A.||Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer|
|US5869100 *||24 Jun 1997||9 Feb 1999||Horacek; H. Joseph||Extended release clonidine formulation (tablet)|
|US5879705 *||18 Abr 1997||9 Mar 1999||Euro-Celtique S.A.||Sustained release compositions of morphine and a method of preparing pharmaceutical compositions|
|US5948437 *||28 May 1997||7 Sep 1999||Zeneca Limited||Pharmaceutical compositions using thiazepine|
|US5958459 *||27 Nov 1995||28 Sep 1999||Purdue Pharma L.P.||Opioid formulations having extended controlled released|
|US5968551 *||27 Jul 1995||19 Oct 1999||Purdue Pharma L.P.||Orally administrable opioid formulations having extended duration of effect|
|US6010718 *||11 Abr 1997||4 Ene 2000||Abbott Laboratories||Extended release formulations of erythromycin derivatives|
|US6030642 *||27 Jun 1997||29 Feb 2000||Horacek; H. Joseph||Extended release clonidine formulation (capsule)|
|US6080428 *||14 Ene 1995||27 Jun 2000||Bova; David J.||Nicotinic acid compositions for treating hyperlipidemia and related methods therefor|
|US6103261 *||6 Ene 1999||15 Ago 2000||Purdue Pharma Lp||Opioid formulations having extended controlled release|
|US6129930 *||6 Mar 1997||10 Oct 2000||Bova; David J.||Methods and sustained release nicotinic acid compositions for treating hyperlipidemia at night|
|US6129933 *||24 Jul 1997||10 Oct 2000||Purdue Pharma Lp||Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer|
|US6143322 *||8 Abr 1997||7 Nov 2000||Purdue Pharma L.P.||Method of treating humans with opioid formulations having extended controlled release|
|US6143328 *||8 Mar 1999||7 Nov 2000||Euro-Celtique, S.A.||Sustained release compositions and a method of preparing pharmaceutical compositions|
|US6210710||28 Abr 1997||3 Abr 2001||Hercules Incorporated||Sustained release polymer blend for pharmaceutical applications|
|US6242003||13 Abr 2000||5 Jun 2001||Novartis Ag||Organic compounds|
|US6264974||7 Jul 1998||24 Jul 2001||Salvagnini Italia Spa||Buccal and sublingual administration of physostigmine|
|US6294195||7 Sep 1999||25 Sep 2001||Purdue Pharma L.P.||Orally administrable opioid formulations having extended duration of effect|
|US6306438||2 Jul 1998||23 Oct 2001||Euro-Celtique, S.A.||Stabilized sustained release tramadol formulations|
|US6372252||28 Abr 2000||16 Abr 2002||Adams Laboratories, Inc.||Guaifenesin sustained release formulation and tablets|
|US6432447||17 May 2001||13 Ago 2002||Novartis Ag||Organic compounds|
|US6551616||13 Oct 1999||22 Abr 2003||Abbott Laboratories||Extended release formulations of erythromycin derivatives|
|US6572885||26 Jun 2001||3 Jun 2003||Euro-Celtique, S.A.||Orally administrable opioid formulations having extended duration of effect|
|US6592901 *||15 Oct 2001||15 Jul 2003||Hercules Incorporated||Highly compressible ethylcellulose for tableting|
|US6645527||19 Oct 2001||11 Nov 2003||Euro-Celtique S.A.||Stabilized sustained release tramadol formulations|
|US6676967||31 Oct 1997||13 Ene 2004||Kos Pharmaceuticals, Inc.||Methods for reducing flushing in individuals being treated with nicotinic acid for hyperlipidemia|
|US6733783||30 Oct 2001||11 May 2004||Euro-Celtique S.A.||Controlled release hydrocodone formulations|
|US6746691||31 Oct 1997||8 Jun 2004||Kos Pharmaceuticals, Inc.||Intermediate release nicotinic acid compositions for treating hyperlipidemia having unique biopharmaceutical characteristics|
|US6806294||23 Abr 2002||19 Oct 2004||Euro-Celtique S.A.||Opioid analgesic|
|US6818229||31 Oct 1997||16 Nov 2004||Kos Pharmaceuticals, Inc.||Intermediate release nicotinic acid compositions for treating hyperlipidemia|
|US6872407||22 Nov 2002||29 Mar 2005||Abbott Laboratories||Extended release formulations of erythromycin derivatives|
|US6905709||12 Nov 2001||14 Jun 2005||Purdue Pharma, Lp||Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer|
|US6955821||15 Abr 2002||18 Oct 2005||Adams Laboratories, Inc.||Sustained release formulations of guaifenesin and additional drug ingredients|
|US7122204||21 Abr 2003||17 Oct 2006||Advancis Pharmaceutical Corporation||Antibiotic composition with inhibitor|
|US7179486||18 May 2001||20 Feb 2007||Nostrum Pharmaceuticals, Inc.||Process for preparing sustained release tablets|
|US7270831||20 Mar 2003||18 Sep 2007||Purdue Pharma L.P.||Orally administrable opioid formulations having extended duration of effect|
|US7282221||14 Nov 2005||16 Oct 2007||Middlebrook Pharmaceuticals, Inc.||Antiviral product, use and formulation thereof|
|US7316821||18 Jun 2004||8 Ene 2008||Purdue Pharma, L.P.|
|US7476403||16 Jun 2004||13 Ene 2009||Andrx Pharmaceuticals, Llc||Oral extended-release composition|
|US7514100||11 Sep 2003||7 Abr 2009||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US7740881||24 Jul 2000||22 Jun 2010||Purdue Pharma Lp||Method of treating humans with opioid formulations having extended controlled release|
|US7838032||4 Abr 2003||23 Nov 2010||Reckitt Benckiser Inc.||Sustained release of guaifenesin|
|US7884122||10 Nov 2009||8 Feb 2011||Shionogi Pharma, Inc.||Extended release formulation and method of treating adrenergic dysregulation|
|US7943174||9 Jun 2004||17 May 2011||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US7985420||4 Abr 2003||26 Jul 2011||Reckitt Benckiser Inc.||Sustained release of guaifenesin combination drugs|
|US7985421||22 Jun 2005||26 Jul 2011||Reckitt Benckiser Inc.||Sustained release formulations of guaifenesin and additional drug ingredients|
|US7998506||23 May 2003||16 Ago 2011||Kos Life Sciences, Inc.||Nicotinic acid compositions for treating hyperlipidemia and related methods therefor|
|US8012504||15 Abr 2003||6 Sep 2011||Reckitt Benckiser Inc.||Sustained release of guaifenesin combination drugs|
|US8062672||12 Ago 2004||22 Nov 2011||Shionogi Inc.||Antibiotic product, use and formulation thereof|
|US8142811||17 Feb 2009||27 Mar 2012||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US8231898||28 Oct 2010||31 Jul 2012||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US8236348||4 Feb 2004||7 Ago 2012||Bennes, Inc.||Long-lasting, flavored dosage forms for sustained release of beneficial agents within the mouth|
|US8246996||20 Ago 2004||21 Ago 2012||Shionogi Inc.||Antibiotic product, use and formulation thereof|
|US8299052||7 May 2007||30 Oct 2012||Shionogi Inc.||Pharmaceutical compositions and methods for improved bacterial eradication|
|US8303987||13 Jul 2010||6 Nov 2012||Novartis Ag||Pharmaceutical compositions comprising fluvastatin|
|US8303988||16 Sep 2010||6 Nov 2012||Shionogi Inc.||Antifungal once-a-day product, use and formulation thereof|
|US8313775||20 Jul 2004||20 Nov 2012||Shionogi Inc.||Antibiotic product, use and formulation thereof|
|US8313776||20 Jul 2004||20 Nov 2012||Shionogi Inc.||Antibiotic product, use and formulation thereof|
|US8357394||8 Dic 2006||22 Ene 2013||Shionogi Inc.||Compositions and methods for improved efficacy of penicillin-type antibiotics|
|US8361499||28 Jun 2012||29 Ene 2013||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US8425936||20 Jul 2004||23 Abr 2013||Shionogi Inc.||Antibiotic product, use and formulation thereof|
|US8460710||14 Sep 2004||11 Jun 2013||Shionogi, Inc.||Antibiotic product, use and formulation thereof|
|US8551520||20 Dic 2012||8 Oct 2013||Purdue Pharma L.P.||Controlled release hydrocodone|
|US8628797||3 Dic 2008||14 Ene 2014||Andrx Pharmaceuticals, Llc||Oral extended-release composition|
|US8647667||24 May 2013||11 Feb 2014||Purdue Pharma, L.P.||Controlled release hydrocodone formulations|
|US8715721||23 May 2013||6 May 2014||Purdue Pharma L.P.||Controlled release hydrocodone|
|US8715727||1 Jul 2005||6 May 2014||Shionogi Inc.||Tablet for pulsed delivery|
|US8758820||11 Ago 2004||24 Jun 2014||Shionogi Inc.||Robust pellet|
|US8778924||4 Dic 2006||15 Jul 2014||Shionogi Inc.||Modified release amoxicillin products|
|US8791160||14 Sep 2012||29 Jul 2014||Ferring B.V.||Tranexamic acid formulations|
|US8809394||9 Jul 2012||19 Ago 2014||Ferring B.V.||Tranexamic acid formulations|
|US8889187||14 Oct 2011||18 Nov 2014||Shionogi Inc.||Once a day amoxicillin product comprising immediate and delayed release dosage forms|
|US8920838||10 Abr 2013||30 Dic 2014||Horizon Pharma Ag||Delayed-release glucocorticoid treatment of rheumatoid disease|
|US8951555||21 Oct 2014||10 Feb 2015||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US8957113||28 Ene 2011||17 Feb 2015||Ferring B.V.||Tranexamic acid formulations|
|US8968777||3 Feb 2006||3 Mar 2015||Ferring B.V.||Tranexamic acid formulations with reduced adverse effects|
|US8975273||11 Sep 2014||10 Mar 2015||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US8980291||30 Dic 2010||17 Mar 2015||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US9023401||23 Dic 2014||5 May 2015||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US9040085||11 Jul 2014||26 May 2015||Jagotec Ag||Delayed release tablet with defined core geometry|
|US9056052||3 Feb 2015||16 Jun 2015||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US9056107||2 Mar 2015||16 Jun 2015||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US9060939||13 Sep 2011||23 Jun 2015||Ferring B.V.||Tranexamic acid formulations|
|US9060940||14 Mar 2014||23 Jun 2015||Purdue Pharma L.P.||Controlled release hydrocodone|
|US9144548||18 Oct 2011||29 Sep 2015||Shionogi Inc.||Antibiotic product, use and formulation thereof|
|US9186332||13 Dic 2012||17 Nov 2015||Jagotec Ag||Delayed release tablet with defined core geometry|
|US9198863||2 Jun 2015||1 Dic 2015||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US9205055||2 Jun 2015||8 Dic 2015||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US9205056||2 Jun 2015||8 Dic 2015||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US9248095||28 Feb 2014||2 Feb 2016||Shaklee Corporation||Nutritional supplement system|
|US9278074||30 Mar 2015||8 Mar 2016||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US9289391||7 May 2015||22 Mar 2016||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US9320717||30 Mar 2015||26 Abr 2016||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US9504681||9 Feb 2016||29 Nov 2016||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US9504699||8 Dic 2014||29 Nov 2016||Hznp Limited||Delayed-release glucocorticoid treatment of rheumatoid disease|
|US9517236||9 Feb 2016||13 Dic 2016||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US9526724||9 Feb 2016||27 Dic 2016||Purdue Pharma L.P.||Controlled release hydrocodone formulations|
|US20020169145 *||18 Mar 2002||14 Nov 2002||Rajen Shah||Sustained release pharmaceutical composition and method of releasing pharmaceutically active agent|
|US20030049318 *||15 Abr 2002||13 Mar 2003||Davis Robert D.||Sustained release formulations of guaifenesin and additional drug ingredients|
|US20030099707 *||12 Nov 2002||29 May 2003||Rudnic Edward M.||Antifungal product, use and formulation thereof|
|US20030133981 *||22 Nov 2002||17 Jul 2003||Notario Gerard F.||Extended release formulations of erythromycin derivatives|
|US20030171419 *||11 Abr 2001||11 Sep 2003||Oskar Kalb||Pharmaceutical compositions comprising fluvastatin|
|US20030180361 *||20 Mar 2003||25 Sep 2003||Benjamin Oshlack||Orally administrable opioid formulations having extended duration of effect|
|US20030215508 *||15 Abr 2003||20 Nov 2003||Davis Robert D.||Sustained release of guaifenesin combination drugs|
|US20030235615 *||21 Abr 2003||25 Dic 2003||Rudnic Edward M.||Antibiotic composition with inhibitor|
|US20040022851 *||4 Abr 2003||5 Feb 2004||Davis Robert D.||Sustained release of guaifenesin combination drugs|
|US20040043073 *||16 Jun 2003||4 Mar 2004||Chih-Ming Chen||Pharmaceutical compositions for drugs having pH-dependent solubility|
|US20040047907 *||11 Sep 2003||11 Mar 2004||Benjamin Oshlack||Controlled release hydrocodone formulations|
|US20040052842 *||1 Jul 2003||18 Mar 2004||Rudnic Edward M.||Antibiotic product, use and formulation thereof|
|US20040096500 *||12 Nov 2003||20 May 2004||Benjamin Oshlack||Controlled release oxycodone compositions|
|US20040121001 *||8 Dic 2003||24 Jun 2004||Benjamin Oshlack||Orally adminstrable opioid formulations having extended duration of effect|
|US20040122065 *||3 Nov 2003||24 Jun 2004||Lerner E. Itzhak||Pharmaceutical compositions and dosage forms for buccal and sublingual delivery of tizanidine and methods of administering tizanidine sublingually or buccally|
|US20040151771 *||4 Feb 2003||5 Ago 2004||Gin Jerry B.||Long-lasting, flavored dosage forms for sustained release of beneficial agents within the mouth|
|US20040170680 *||2 May 2002||2 Sep 2004||Benjamin Oshlack||Once-a-day oxycodone formulations|
|US20040185098 *||24 Mar 2004||23 Sep 2004||Benjamin Oshlack||Controlled release oxycodone compositions|
|US20040228917 *||18 Jun 2004||18 Nov 2004||Purdue Pharma Lp|
|US20040247669 *||4 Feb 2004||9 Dic 2004||Gin Jerry B.||Long-lasting, flavored dosage forms for sustained release of beneficial agents within the mouth|
|US20040266807 *||9 Jun 2004||30 Dic 2004||Euro-Celtique, S.A.||Controlled release hydrocodone formulations|
|US20050019401 *||20 Jul 2004||27 Ene 2005||Burnside Beth A.||Antibiotic product, use and formulation thereof|
|US20050019402 *||20 Jul 2004||27 Ene 2005||Burnside Beth A.||Antibiotic product, use and formulation thereof|
|US20050019403 *||20 Jul 2004||27 Ene 2005||Burnside Beth A.||Antibiotic product, use and formulation thereof|
|US20050037071 *||11 Ago 2004||17 Feb 2005||Cao Bruce X.||Robust pellet|
|US20050037076 *||12 Ago 2004||17 Feb 2005||Burnside Beth A.||Antibiotic product, use and formulation thereof|
|US20050048114 *||20 Ago 2004||3 Mar 2005||Burnside Beth A.||Antibiotic product, use and formulation thereof|
|US20050058706 *||26 Abr 2004||17 Mar 2005||Grunenthal Gmbh||Delayed release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol|
|US20050058708 *||14 Sep 2004||17 Mar 2005||Burnside Beth A.||Antibiotic product, use and formulation thereof|
|US20050064033 *||5 Nov 2004||24 Mar 2005||Notario Gerard F.||Extended release formulations of erythromycin derivatives|
|US20050064034 *||16 Jun 2004||24 Mar 2005||Andrx Pharmaceuticals, Llc||Oral extended-release composition|
|US20050118257 *||23 May 2003||2 Jun 2005||Bova David J.||Nicotinic acid compositions for treating hyperlipidemia and related methods therefor|
|US20050142187 *||23 Dic 2004||30 Jun 2005||Treacy Donald J.Jr.||Enhanced absorption of modified release dosage forms|
|US20050214368 *||19 Abr 2005||29 Sep 2005||Biovail Corp||Controlled release formulations using intelligent polymers|
|US20050238714 *||6 May 2005||27 Oct 2005||Rudnic Edward M||Anti-fungal composition|
|US20050276852 *||22 Jun 2005||15 Dic 2005||Adams Laboratories, Inc.||Sustained release formulations of guaifenesin and additional drug ingredients|
|US20060003005 *||1 Jul 2005||5 Ene 2006||Bruce Cao||Tablet for pulsed delivery|
|US20060039969 *||28 Mar 2005||23 Feb 2006||Notario Gerard F||Extended release formulations of erythromycin derivatives|
|US20060057210 *||17 Ago 2005||16 Mar 2006||Purdue Pharma L.P.||Controlled release oxycodone compositions|
|US20060099263 *||22 Dic 2005||11 May 2006||Edgren David E||Antidepressant dosage form|
|US20060110455 *||14 Nov 2005||25 May 2006||Rudnic Edward M||Antiviral product, use and formulation thereof|
|US20060127474 *||3 Feb 2006||15 Jun 2006||Oskar Kalb||Pharmaceutical compositions comprising fluvastatin|
|US20060127476 *||3 Feb 2006||15 Jun 2006||Xanodyne Pharmaceuticals, Inc.||Tranexamic acid formulations with reduced adverse effects|
|US20060159754 *||21 Mar 2006||20 Jul 2006||Rajen Shah||Sustained release pharmaceutical composition and method of releasing pharmaceutically active agent|
|US20060269604 *||8 Ago 2006||30 Nov 2006||Purdue Pharma L.P.||Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level|
|US20070224270 *||4 Jun 2007||27 Sep 2007||Bova David J||Nicotinic Acid Compositions For Treating Hyperlipidemia and Related Methods Therefor|
|US20070225341 *||4 Jun 2007||27 Sep 2007||Bova David J||Nicotinic Acid Compositions For Treating Hyperlipidemia and Related Methods Therefor|
|US20070225342 *||4 Jun 2007||27 Sep 2007||Bova David J||Nicotinic Acid Compositions For Treating Hyperlipidemia and Related Methods Therefor|
|US20070232667 *||12 Jun 2007||4 Oct 2007||Eugenio Cefali||Methods for Treating Hyperlipidemia With Intermediate Release Nicotinic Acid Compositions Having Unique Biopharmaceutical Characteristics|
|US20070237819 *||4 Jun 2007||11 Oct 2007||Bova David J||Nicotinic Acid Compositions For Treating Hyperlipidemia and Related Methods Therefor|
|US20070237832 *||8 Jun 2007||11 Oct 2007||Purdue Pharma L.P.||Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level|
|US20070237833 *||8 Jun 2007||11 Oct 2007||Purdue Pharma L.P.||Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level|
|US20070275062 *||26 Mar 2007||29 Nov 2007||Benjamin Oshlack||Controlled release oxycodone compositions|
|US20070293580 *||5 Jun 2007||20 Dic 2007||Malcolm Hill||Methods for Buccal, Lingual or Sublingual Dosing Regimens of Epinephrine for the Treatment of Allergic Emergencies|
|US20070293581 *||5 Jun 2007||20 Dic 2007||Malcolm Hill||Methods for Buccal, Lingual or Sublingual Dosing Regimens of Epinephrine for the Treatment of Allergic Emergencies|
|US20070293582 *||5 Jun 2007||20 Dic 2007||Malcolm Hill||Epinephrine dosing regimens comprising buccal, lingual or sublingual and injectable dosage forms|
|US20080020032 *||20 Jul 2007||24 Ene 2008||Michael Crowley||Hydrophobic abuse deterrent delivery system for hydromorphone|
|US20080031963 *||8 Jun 2007||7 Feb 2008||Purdue Pharma L.P.|
|US20080045573 *||15 Ago 2007||21 Feb 2008||Bova David J||Methods and Sustained Release Nicotinic Acid Compositions for Treating Hyperlipidemia|
|US20080050430 *||7 May 2007||28 Feb 2008||Flanner Henry H||Pharmaceutical compositions and methods for improved bacterial eradication|
|US20080055036 *||29 Ago 2006||6 Mar 2008||International Business Machines Corporation||Electrical component tuned by conductive layer deletion|
|US20080075768 *||20 Jul 2007||27 Mar 2008||Vaughn Jason M||Hydrophobic opioid abuse deterrent delivery system using opioid antagonists|
|US20080075770 *||20 Jul 2007||27 Mar 2008||Vaughn Jason M||Hydrophilic abuse deterrent delivery system|
|US20080075771 *||20 Jul 2007||27 Mar 2008||Vaughn Jason M||Hydrophilic opioid abuse deterrent delivery system using opioid antagonists|
|US20080075781 *||17 May 2007||27 Mar 2008||Purdue Pharma Lp||Controlled release oxycodone compositions|
|US20080132478 *||4 Dic 2006||5 Jun 2008||Flanner Henry H||Modified release amoxicillin products|
|US20080181941 *||17 Ago 2007||31 Jul 2008||Purdue Pharma L.P.||Orally administrable opioid formulations having extended duration of effect|
|US20090068269 *||10 Sep 2008||12 Mar 2009||Purdue Pharma L.P.||Orally adminstrable opioid formulations having extended duration of effect|
|US20090081291 *||26 Sep 2007||26 Mar 2009||Gin Jerry B||Sustained Release Dosage Forms For Delivery of Agents to an Oral Cavity of a User|
|US20090081294 *||26 Sep 2007||26 Mar 2009||Gin Jerry B||Sustained release dosage form for lubricating an oral cavity|
|US20090087490 *||6 Jun 2008||2 Abr 2009||Addrenex Pharmaceuticals, Inc.||Extended release formulation and method of treating adrenergic dysregulation|
|US20090124563 *||3 Dic 2008||14 May 2009||Boying Li||Oral extended-release composition|
|US20090155392 *||16 Dic 2008||18 Jun 2009||Bret David Nelson||Methods and Systems for Sublingual Guarana Administration|
|US20100034876 *||15 Oct 2009||11 Feb 2010||Purdue Pharma L.P.||Controlled release oxycodone compositions|
|US20100063123 *||10 Nov 2009||11 Mar 2010||Addrenex Pharmaceuticals, Inc.||Extended release formulation and method of treating adrenergic dysregulation|
|US20100092570 *||15 Oct 2009||15 Abr 2010||Purdue Pharma L.P.||Controlled release oxycodone compositions|
|US20100143533 *||3 Feb 2010||10 Jun 2010||Shaklee Corporation||Nutritional supplement system|
|US20100172991 *||23 Dic 2009||8 Jul 2010||Henry Joseph Horacek||Extended Release Formulation and Methods of Treating Adrenergic Dysregulation|
|US20100209351 *||8 Dic 2009||19 Ago 2010||Sackler Richard S|
|US20100209510 *||16 Sep 2009||19 Ago 2010||Henry Joseph Horacek||Extended Release Formulation and Method of Treating Adrenergic Dysregulation|
|US20100209514 *||8 Dic 2009||19 Ago 2010||Sackler Richard S||Method of treating pain by administering 24 hour oral oploid formulations exhibiting rapid rate of initial rise of plasma drug level|
|US20100222312 *||26 Ene 2010||2 Sep 2010||Nitec Pharma Ag||Delayed-release glucocorticoid treatment of asthma|
|US20100280117 *||29 Abr 2010||4 Nov 2010||Xanodyne Pharmaceuticals, Inc.||Menorrhagia Instrument and Method for the Treatment of Menstrual Bleeding Disorders|
|US20100303919 *||13 Jul 2010||2 Dic 2010||Oskar Kalb||Pharmaceutical compositions comprising fluvastatin|
|US20100311802 *||16 Jul 2010||9 Dic 2010||Rajen Shah||Sustained release pharmaceutical composition and method of releasing pharmaceutically active agent|
|US20110052689 *||5 Nov 2010||3 Mar 2011||Reckitt Benckiser Inc.||Sustained release of guaifenesin|
|US20110065718 *||16 Sep 2010||17 Mar 2011||Victory Pharma, Inc.||Antifungal Product, Use and Formulation Thereof|
|US20110230559 *||28 Ene 2011||22 Sep 2011||Ferring B.V.||Tranexamic Acid Formulations|
|DE3020724A1 *||31 May 1980||29 Ene 1981||Forest Laboratories||Therapeutische praeparate mit retardwirkung|
|DE3246492A1 *||16 Dic 1982||30 Jun 1983||Forest Laboratories||Verfahren zur herstellung therapeutischer praeparate auf der basis von hydroxypropylmethylzellulose mit verlaengertem freisetzungsverlauf|
|DE3309516A1 *||17 Mar 1983||1 Dic 1983||Forest Laboratories||Verfahren zur herstellung therapeutischer praeparate mit anhaltender freisetzung auf der basis von hydroxypropylmethylzellulose mit hohem molekulargewicht|
|DE3834794A1 *||12 Oct 1988||19 Abr 1990||F Schielein||Composition for oral administration to treat psoriasis|
|EP2803357A2||27 Jun 2005||19 Nov 2014||The Johns-Hopkins University||Angiogenesis inhibitors|
|EP3042654A1||20 Ene 2012||13 Jul 2016||Bionevia Pharmaceuticals Inc.||Modified release compositions of epalrestat or a derivative thereof and methods for using the same|
|WO1985004100A1 *||22 Feb 1985||26 Sep 1985||American Home Products Corporation||Sustained release pharmaceutical capsules|
|WO2005060941A1 *||21 Dic 2004||7 Jul 2005||Sandoz Ag||Extended release antibiotic composition|
|WO2010042163A2||6 Oct 2009||15 Abr 2010||The Johns Hopkins University||Quinoline compounds as inhibitors of angiogenesis, human methionine aminopeptidase, and sirt1, and methods of treating disorders|
|WO2014168874A2||7 Abr 2014||16 Oct 2014||The Broad Institute, Inc.||Compositions and methods for personalized neoplasia vaccines|
|WO2016100975A1||21 Dic 2015||23 Jun 2016||Massachsetts Institute Ot Technology||Molecular biomarkers for cancer immunotherapy|
|Clasificación de EE.UU.||424/469, 424/436, 424/430, 514/777, 424/480|