CA1316108C - Formulation for preparing sustained release drugs for oral administration - Google Patents
Formulation for preparing sustained release drugs for oral administrationInfo
- Publication number
- CA1316108C CA1316108C CA000531406A CA531406A CA1316108C CA 1316108 C CA1316108 C CA 1316108C CA 000531406 A CA000531406 A CA 000531406A CA 531406 A CA531406 A CA 531406A CA 1316108 C CA1316108 C CA 1316108C
- Authority
- CA
- Canada
- Prior art keywords
- tablets
- release
- xanthan gum
- matrix
- sustained release
- 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 - Fee Related
Links
Classifications
-
- 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
-
- 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
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
Abstract
ABSTRACT
Pharmaceutical formulations are disclosed, adapted for preparing solid oral dosage forms (tablets, capsules, lozenges, etc.) having a regular and sustained release after administration. Said formulations comprise one or more active substances and a retarding base or matrix consisting of a polysaccharide of natural origin, alone or mixed with one or more natural or synthetic polymers which may be used to modify the release pattern so as to obtain a therapeutically effective formulation.
Pharmaceutical formulations are disclosed, adapted for preparing solid oral dosage forms (tablets, capsules, lozenges, etc.) having a regular and sustained release after administration. Said formulations comprise one or more active substances and a retarding base or matrix consisting of a polysaccharide of natural origin, alone or mixed with one or more natural or synthetic polymers which may be used to modify the release pattern so as to obtain a therapeutically effective formulation.
Description
~31~
"FORMULATION FOR PREPARING SUSTAINED RELEASE DRUGS FOR ORAL
ADMINISTRATION"
The present invention relates to pharmaceutical formulations adapted to prepare solid oral dosage forms, such as capsules, tablets, lozenges and the like, having a regular and sustained release after administration.
The advantages of the sustained release or retard drugs are well known 5 since a long time, because delaying the dissolution of the active substance, the absorption time in the gastrointestinal tract is extended, thus prolonging the therapeutic effect, at the same time avoiding or at least reducing the side effects.
For this purpose a retard formulation has to meet some criteria, namely causing a uniform and constant dissolution and being effective for an extended lû period of time. It is also important that such a formulation be simple to be made, the manufacturing process be reproducible and may be used for a high number oF
different substances.
- ~
' . .:' ' '.'''';':
. .
;
"FORMULATION FOR PREPARING SUSTAINED RELEASE DRUGS FOR ORAL
ADMINISTRATION"
The present invention relates to pharmaceutical formulations adapted to prepare solid oral dosage forms, such as capsules, tablets, lozenges and the like, having a regular and sustained release after administration.
The advantages of the sustained release or retard drugs are well known 5 since a long time, because delaying the dissolution of the active substance, the absorption time in the gastrointestinal tract is extended, thus prolonging the therapeutic effect, at the same time avoiding or at least reducing the side effects.
For this purpose a retard formulation has to meet some criteria, namely causing a uniform and constant dissolution and being effective for an extended lû period of time. It is also important that such a formulation be simple to be made, the manufacturing process be reproducible and may be used for a high number oF
different substances.
- ~
' . .:' ' '.'''';':
. .
;
- 2 - 1 3 ~
There arè several known methods for preparing retard products in the form of solid oral dosage such as tablets or capsules. Among these rnethods, delaying hydrophilic matrices are often used because the manufacture of finished form is simple and reproducible3 it is possible to obtain a gradual and continuous release, 5 they can be applied to many drugs and are economically advantageous.
Hydrophilic matrix is defined a homogeneous mixture of substances, substantially comprising polymers which are slowly dissolved in water and then receiving a well defined form by compression or encapsulation. When the tablet is contacted with water or aqueous based dissolution media as the gastro-intestinal 10 juices, the hydrophilic polymers give rise to the formation of a gelatinous surface layer, through which water slowly penetrates inside, hydrating and swelling the polymer; then the polymer in the gel form, gradually goes in solution, first the outermost layer and thereafter the inner layers until it is totally dissolved and disappears.
In this way the active substance is totally and slowly released by two contemporaneous mechanisms, namely diffusion through the gelatinous layer and gel erosion.
While the first of these release mechanisms prevails in case of drugs very solubnle in the dissolution medium, the second prevails in case of poorly soluble 20 drugs.
The polymers suitable for the preparation of hydrophilic retard matrices are relatively few, but there are already patents and publications on this subject matter.
U.S. patents N 4,259,341 to Lowey, N3,870,790 to Lowey et al, 2C N4,226,849 to Schor and N 4,357,469 to Schor relate to the preparation of tablets , ,; . ,.-1316 1 ~8 with a hydrophilic matrix comprising hyclroxypropylmethylcellu-lose, alone or mixed with other cellulose derivatives, having undergone particular treatment such as high drying, humidifi-cation hydrolysis, oxidation.
Also U.S. patents Nos. 4,369,172 and 4,389,393 to Schor et al relate to the use of one or more tyeps and well defined quantities of hydroxyprop~lmethylcellulose alone or mixed with C methylcellulose and/or so ium carboxymethylcellulose.
U.S. patents Nos. ~ ~r44~ and 4,126,672 to Sheth et al relate to the use of hydroxypropylemthylcellulose for pre-paring tablets and more particularly capsules with hydrophilic matrix having such a composition that they remain floating in the gastric juices.
The article titled "A review of cellulose ethers in hydrophilic matrices for oral controlled release dosage forms" by D.A. Alderman, published on Int. Journal Pharm.
Techn. & Prod. Mfr. 5(3) 1-9, 1984, widely deals with the use of hydroxypropylmethylcellulose for preparing retard hy-drophilic matrices and studies the influence of the drug re-lease, of several parameters characteristic of hydroxypropyl-methylcellulose such as molecular weight, substitution degree, grain size distribution, velocity of hydration.
The present invention relates to the use of a hydrophilic polymer of natural origin, namely xanthan gum as the main con-stituent of formulations adapted to prepare hydrophilic retardmatrices for the administration of drugs in the form of tablets, lozenges, capsules and so on. The main feature of this invention consists indeed in using xanthan gum to obtain retard matrices, this object having been /~
::::
~4--13~3 ~
attained up to now only u.sing hydroxypropylmethylcellulose as single or main hydrophilic polymer. In the relevant litera-ture moreover the xanthan gum is generally used in water sol-ution as thickeners to stabilize emulsions, suspensions, creams, latices and the like, and its use as retarding agent for preparing solid matrices is never cited.
FR-A-2.143.059 concerns a pharmaceutical formulation in which the sustained release is obtained by addition of galactomannanes, i.e. guar gum and locust bean gum that are part of the great family of the polysaccharides, but they differ from the xanthan gum, mentioned in the present inven-tion, both as behaviour and application, because they differ chemically as they are composed of galactose and mannose units while the xanthan gum is composed of mannose, glucose and glucuronic acid (as a mixed potassium, sodium and calcium salt), and as origin being obtained from plants instead of microorganisms.
GB-A-2.055.577 describes a complex sustained release pharmaceutical composition made of a compressed core that comprises a drug and a polymer mixture comprising (A) a water-soluble polymer (xanthan gum, karaya gum) used as a dissolution promoter and a water-insoluble polymer (ethylcel-lulose) used as a retarding agent or (B) hydroxypropylmethyl-cellulose and hydroxypropylcellulose, and a sugar coating comprising sugar and part of at least one of the drugs con-tained in the core.
The present invention concerns a simple pharma-ceutical composition consisting basically of a drug and ~' ~ 3 ~
a matrix made of xanthan gum as retarding agent with another well defined water-soluble polymer like hydroxypropylmekhyl-cellulose, according to the characterizing part of Claim 1.
European paten-t application EP-A2-0234670 published on September 2, 1987 concerns a sustained release tablet wherein the matrix comprises at least 75% by weight of xanthan gum. The addition to the sustained release carrier of a minor proportion of another polymer having sustained release properties is also mentioned but without any care about the kind and solubility of the polymer that can be both water soluble or insoluble.
On the contrary, the matrix claimed in the present invention is characterized in that the percentage by weight of the matrix components is above 50% but below 75% of xanthan gum and up to 50% of one or more of well precised hydrophylic polymers. The percentages of xanthan gum and hydrophylic polymers falling outside these ranges are explic-itly disclaimed from the present invention.
The addition of these hydrophylic polymers character-izes the matrix, because it has a synergic effect on the sus-taining release properties of xanthan gum and facilitates the formation of the gel layer through which the drug diffuses.
In fact in the case of soluble drugs, like in the present invention, the drug is released mainly by diffusion from the gel layer formed by the hydrophilic polymers as soon as they come in contact with water or the gastro-intestinal iuices while in the case of insoluble drugs, these are released only by exposure through tablet erosion and in the above mentioned , .
, ' , ' - .
~ b~ 13 ~
prior patent application, 16 out of 18 Examples use insoluble drugs.
According to the present invention it was indeed found that use of polysaccharides of natural origin allows to obtain matrices giving rise to a sustained and gradual drug release; more'over by varying the ~uantity of the poly-saccharide of natural origin in the formulation according to the solubility and dosage of the drug, it is possible to change the pattern of in vitro drug release. As a matter of fact polysaccharides of natural origin, which are hydrophilic polymers of high molecular weight, when they are contacted by water or gastrointestinal juices, give rapid rise to the formation of a gelatinous surface layer controlling the fur-ther diffusion of water or gastrointestinal juices to the interior and consequently the drug release.
Water or juices penetrate inside the matrix in sub-sequent layers gradually transforming the polymer into a gel-atinous mass and then dissolving it while active substance is at the same time released.
Another advantage of polysaccharides of natural ori-gin is that they allow to extend release of a great number of drugs, irrespective of their dosage and solubility, by em-ploying economical and reproducible manufacturing processes.
Still another advantage is given by the possibility of preparing formulations giving rise to retard matrices releasing the drug even in very long times that may even reach 24 hours so as to allow only one single administration per day.
~ ~5--1 3 ~
Xanthan gum is a high molecular natural carbohydrate and more particularly an exocellular biopolysaccharide pro-duced by a fermentation process of the microorganism Xantho-monas campestris. Structure, molecular weight and properties of dissolution of this natural polymer are constant and re-producible under strictly controlled operative conditions.
Xanthan gum, known also under the trade names of Keltrol and Kelzan ~, is used in many fields, such as the food, drug and cosmetic field. In these cases -the thickening and stabilizing property of emulsions or suspensions given by xanthan gum in solution is used.
With the present invention it was found that i-t is possible to utilize the properties of xanthan gum even for solid formulations of drugs, using it for preparing hydro-philic matrices in which xanthan gum has the effect of delay-ing the drug dissolution.
In addition to xanthan gum, the matrix comprises other natural or synthetic polymers, having the effect of varying the drug release curve so as to obtain those more adapted to reach the maximum in vivo bioavailability and efficiency thereof.
Therefore xanthan yum is mixed with polymers hydrat-ing and dissolving in water such as methylcellulose, hydroxy-ethylcellulose, gum arabic, polyvinylpyrrolidone, gelatine, hydroxypropylmethylcellulose, hydroxypropylcellulose.
Matrix is therefore characterized in that the percen-tage by weight of xanthan gum is above 50 but below 75% and is mixed with a percentage up to 50% of one or more of the ~ ~ .
~,...
1 3 ~
above mentioned polymers hydrating and dissolving in water.
The retarding matrix is mixed in a suitable apparatus with the drug or even more drugs, which are intended to be administered in a sustained release form. Among the possible drugs, the following are cited as illustrative non limiting examples only:' adrenergic amines (ethylephrine, phenylephrine, phenylpropan-olamine, d-pseudoephedrine), antispasmodics (scopolamine and other belladonna alkaloids, papaverine and its derivatives), antihistaminics (bronchopheniramine, chloropheniramine, diphenylpyraline, dimenhydrinate), anorexics (norpseudoephed-rine, phenermine, diethylpropione, phenfluramine), antiasth-matics (theophylline, sulbutamol, terbutaline), antianginics (isosorbide - 5 - mononitrate, isosorbide dinitrate, pent-aerythritol tetranitrate, nitroglycerin, nifedipine, dilthia-zem), antiflammatories and antipyretics (indomethacine, ibuprofen, ketoprofen, acetylsalicylic acid, paracetamol, phenacetine), hypotensives (nifedipine, hydrolazine, prazo-sine, verapamil), antidepressants (anitryptiline, lithium salt), antitussives (dextromethorphane, noscapine, codeine), gastroenterics (cimetidine, ranitidine, methoclopramide), antiarrhythmics (procainamide, lidocaine, flecainide, propo-phenone), analgesics (morphine), vitamins (ascorbic acid) and their salts used in the pharmaceutical field.
In addition to polymers and drugs, in the formulation there may be also inert excipients commonly used by men skilled in the art to improve the characteristics of said formulation.
~.~
~ 3 ~
Thus for instance, lubricants, dyestufEs, sweeteners, flavouring agents, inert excipients and so forth may be added in the preparation of tablets in order to improve flowance of powders, appearance, taste, dosage precision and the like.
The quantity of matrix u.sed to delay drug release may therefore be varied in a broad interval, depending whether the formulation comprises only drug and matrix or other excipients are present in a more or less high amount accord-ing to the high or low level of solubility and/or the high or low dosage of the active substance.
Therefore said matrix may vary between 10 and 80% by weight of the formulation and preferably between 20 and 60%
by weight.
The following examples are intended to better clarify the invention and it is to be understood that they are not limiting the scope of the invention, as many variations may be readily apparent to a man skilled in the art.
Sustained release tablets of theophylline (dosage 350 mg) were prepared, containing the percentages of delaying substances set forth in the following table:
- . __ Example No. Xanthan gum % ~ydroxypropylcellulose %
. .
1 19.8 9.9 .
2 10.1 10.1 Tablets of 350 mg each were prepared with the follow-ing excipients:
i~3 -8- 13~
Example 1 Example 2 Ingredients g mg/tablet g mg/tablet 1) Theophylline 105.0350.0 105.0 350.0 2) Xanthan gum 30.O100.O 15.0 50.O
There arè several known methods for preparing retard products in the form of solid oral dosage such as tablets or capsules. Among these rnethods, delaying hydrophilic matrices are often used because the manufacture of finished form is simple and reproducible3 it is possible to obtain a gradual and continuous release, 5 they can be applied to many drugs and are economically advantageous.
Hydrophilic matrix is defined a homogeneous mixture of substances, substantially comprising polymers which are slowly dissolved in water and then receiving a well defined form by compression or encapsulation. When the tablet is contacted with water or aqueous based dissolution media as the gastro-intestinal 10 juices, the hydrophilic polymers give rise to the formation of a gelatinous surface layer, through which water slowly penetrates inside, hydrating and swelling the polymer; then the polymer in the gel form, gradually goes in solution, first the outermost layer and thereafter the inner layers until it is totally dissolved and disappears.
In this way the active substance is totally and slowly released by two contemporaneous mechanisms, namely diffusion through the gelatinous layer and gel erosion.
While the first of these release mechanisms prevails in case of drugs very solubnle in the dissolution medium, the second prevails in case of poorly soluble 20 drugs.
The polymers suitable for the preparation of hydrophilic retard matrices are relatively few, but there are already patents and publications on this subject matter.
U.S. patents N 4,259,341 to Lowey, N3,870,790 to Lowey et al, 2C N4,226,849 to Schor and N 4,357,469 to Schor relate to the preparation of tablets , ,; . ,.-1316 1 ~8 with a hydrophilic matrix comprising hyclroxypropylmethylcellu-lose, alone or mixed with other cellulose derivatives, having undergone particular treatment such as high drying, humidifi-cation hydrolysis, oxidation.
Also U.S. patents Nos. 4,369,172 and 4,389,393 to Schor et al relate to the use of one or more tyeps and well defined quantities of hydroxyprop~lmethylcellulose alone or mixed with C methylcellulose and/or so ium carboxymethylcellulose.
U.S. patents Nos. ~ ~r44~ and 4,126,672 to Sheth et al relate to the use of hydroxypropylemthylcellulose for pre-paring tablets and more particularly capsules with hydrophilic matrix having such a composition that they remain floating in the gastric juices.
The article titled "A review of cellulose ethers in hydrophilic matrices for oral controlled release dosage forms" by D.A. Alderman, published on Int. Journal Pharm.
Techn. & Prod. Mfr. 5(3) 1-9, 1984, widely deals with the use of hydroxypropylmethylcellulose for preparing retard hy-drophilic matrices and studies the influence of the drug re-lease, of several parameters characteristic of hydroxypropyl-methylcellulose such as molecular weight, substitution degree, grain size distribution, velocity of hydration.
The present invention relates to the use of a hydrophilic polymer of natural origin, namely xanthan gum as the main con-stituent of formulations adapted to prepare hydrophilic retardmatrices for the administration of drugs in the form of tablets, lozenges, capsules and so on. The main feature of this invention consists indeed in using xanthan gum to obtain retard matrices, this object having been /~
::::
~4--13~3 ~
attained up to now only u.sing hydroxypropylmethylcellulose as single or main hydrophilic polymer. In the relevant litera-ture moreover the xanthan gum is generally used in water sol-ution as thickeners to stabilize emulsions, suspensions, creams, latices and the like, and its use as retarding agent for preparing solid matrices is never cited.
FR-A-2.143.059 concerns a pharmaceutical formulation in which the sustained release is obtained by addition of galactomannanes, i.e. guar gum and locust bean gum that are part of the great family of the polysaccharides, but they differ from the xanthan gum, mentioned in the present inven-tion, both as behaviour and application, because they differ chemically as they are composed of galactose and mannose units while the xanthan gum is composed of mannose, glucose and glucuronic acid (as a mixed potassium, sodium and calcium salt), and as origin being obtained from plants instead of microorganisms.
GB-A-2.055.577 describes a complex sustained release pharmaceutical composition made of a compressed core that comprises a drug and a polymer mixture comprising (A) a water-soluble polymer (xanthan gum, karaya gum) used as a dissolution promoter and a water-insoluble polymer (ethylcel-lulose) used as a retarding agent or (B) hydroxypropylmethyl-cellulose and hydroxypropylcellulose, and a sugar coating comprising sugar and part of at least one of the drugs con-tained in the core.
The present invention concerns a simple pharma-ceutical composition consisting basically of a drug and ~' ~ 3 ~
a matrix made of xanthan gum as retarding agent with another well defined water-soluble polymer like hydroxypropylmekhyl-cellulose, according to the characterizing part of Claim 1.
European paten-t application EP-A2-0234670 published on September 2, 1987 concerns a sustained release tablet wherein the matrix comprises at least 75% by weight of xanthan gum. The addition to the sustained release carrier of a minor proportion of another polymer having sustained release properties is also mentioned but without any care about the kind and solubility of the polymer that can be both water soluble or insoluble.
On the contrary, the matrix claimed in the present invention is characterized in that the percentage by weight of the matrix components is above 50% but below 75% of xanthan gum and up to 50% of one or more of well precised hydrophylic polymers. The percentages of xanthan gum and hydrophylic polymers falling outside these ranges are explic-itly disclaimed from the present invention.
The addition of these hydrophylic polymers character-izes the matrix, because it has a synergic effect on the sus-taining release properties of xanthan gum and facilitates the formation of the gel layer through which the drug diffuses.
In fact in the case of soluble drugs, like in the present invention, the drug is released mainly by diffusion from the gel layer formed by the hydrophilic polymers as soon as they come in contact with water or the gastro-intestinal iuices while in the case of insoluble drugs, these are released only by exposure through tablet erosion and in the above mentioned , .
, ' , ' - .
~ b~ 13 ~
prior patent application, 16 out of 18 Examples use insoluble drugs.
According to the present invention it was indeed found that use of polysaccharides of natural origin allows to obtain matrices giving rise to a sustained and gradual drug release; more'over by varying the ~uantity of the poly-saccharide of natural origin in the formulation according to the solubility and dosage of the drug, it is possible to change the pattern of in vitro drug release. As a matter of fact polysaccharides of natural origin, which are hydrophilic polymers of high molecular weight, when they are contacted by water or gastrointestinal juices, give rapid rise to the formation of a gelatinous surface layer controlling the fur-ther diffusion of water or gastrointestinal juices to the interior and consequently the drug release.
Water or juices penetrate inside the matrix in sub-sequent layers gradually transforming the polymer into a gel-atinous mass and then dissolving it while active substance is at the same time released.
Another advantage of polysaccharides of natural ori-gin is that they allow to extend release of a great number of drugs, irrespective of their dosage and solubility, by em-ploying economical and reproducible manufacturing processes.
Still another advantage is given by the possibility of preparing formulations giving rise to retard matrices releasing the drug even in very long times that may even reach 24 hours so as to allow only one single administration per day.
~ ~5--1 3 ~
Xanthan gum is a high molecular natural carbohydrate and more particularly an exocellular biopolysaccharide pro-duced by a fermentation process of the microorganism Xantho-monas campestris. Structure, molecular weight and properties of dissolution of this natural polymer are constant and re-producible under strictly controlled operative conditions.
Xanthan gum, known also under the trade names of Keltrol and Kelzan ~, is used in many fields, such as the food, drug and cosmetic field. In these cases -the thickening and stabilizing property of emulsions or suspensions given by xanthan gum in solution is used.
With the present invention it was found that i-t is possible to utilize the properties of xanthan gum even for solid formulations of drugs, using it for preparing hydro-philic matrices in which xanthan gum has the effect of delay-ing the drug dissolution.
In addition to xanthan gum, the matrix comprises other natural or synthetic polymers, having the effect of varying the drug release curve so as to obtain those more adapted to reach the maximum in vivo bioavailability and efficiency thereof.
Therefore xanthan yum is mixed with polymers hydrat-ing and dissolving in water such as methylcellulose, hydroxy-ethylcellulose, gum arabic, polyvinylpyrrolidone, gelatine, hydroxypropylmethylcellulose, hydroxypropylcellulose.
Matrix is therefore characterized in that the percen-tage by weight of xanthan gum is above 50 but below 75% and is mixed with a percentage up to 50% of one or more of the ~ ~ .
~,...
1 3 ~
above mentioned polymers hydrating and dissolving in water.
The retarding matrix is mixed in a suitable apparatus with the drug or even more drugs, which are intended to be administered in a sustained release form. Among the possible drugs, the following are cited as illustrative non limiting examples only:' adrenergic amines (ethylephrine, phenylephrine, phenylpropan-olamine, d-pseudoephedrine), antispasmodics (scopolamine and other belladonna alkaloids, papaverine and its derivatives), antihistaminics (bronchopheniramine, chloropheniramine, diphenylpyraline, dimenhydrinate), anorexics (norpseudoephed-rine, phenermine, diethylpropione, phenfluramine), antiasth-matics (theophylline, sulbutamol, terbutaline), antianginics (isosorbide - 5 - mononitrate, isosorbide dinitrate, pent-aerythritol tetranitrate, nitroglycerin, nifedipine, dilthia-zem), antiflammatories and antipyretics (indomethacine, ibuprofen, ketoprofen, acetylsalicylic acid, paracetamol, phenacetine), hypotensives (nifedipine, hydrolazine, prazo-sine, verapamil), antidepressants (anitryptiline, lithium salt), antitussives (dextromethorphane, noscapine, codeine), gastroenterics (cimetidine, ranitidine, methoclopramide), antiarrhythmics (procainamide, lidocaine, flecainide, propo-phenone), analgesics (morphine), vitamins (ascorbic acid) and their salts used in the pharmaceutical field.
In addition to polymers and drugs, in the formulation there may be also inert excipients commonly used by men skilled in the art to improve the characteristics of said formulation.
~.~
~ 3 ~
Thus for instance, lubricants, dyestufEs, sweeteners, flavouring agents, inert excipients and so forth may be added in the preparation of tablets in order to improve flowance of powders, appearance, taste, dosage precision and the like.
The quantity of matrix u.sed to delay drug release may therefore be varied in a broad interval, depending whether the formulation comprises only drug and matrix or other excipients are present in a more or less high amount accord-ing to the high or low level of solubility and/or the high or low dosage of the active substance.
Therefore said matrix may vary between 10 and 80% by weight of the formulation and preferably between 20 and 60%
by weight.
The following examples are intended to better clarify the invention and it is to be understood that they are not limiting the scope of the invention, as many variations may be readily apparent to a man skilled in the art.
Sustained release tablets of theophylline (dosage 350 mg) were prepared, containing the percentages of delaying substances set forth in the following table:
- . __ Example No. Xanthan gum % ~ydroxypropylcellulose %
. .
1 19.8 9.9 .
2 10.1 10.1 Tablets of 350 mg each were prepared with the follow-ing excipients:
i~3 -8- 13~
Example 1 Example 2 Ingredients g mg/tablet g mg/tablet 1) Theophylline 105.0350.0 105.0 350.0 2) Xanthan gum 30.O100.O 15.0 50.O
3) Hydroxypropyl-cellulose 15.050.0 15.0 50.0 4) Fumed silica 0.6 2.0 0.6 2.0 5) Magnesium stearate 0.9 3.0 0.9 3.0 The ingredients 1, 2 and 3 were mixed for 15 minutes.
Then ingredient 4 was added and after further 15 minutes of mixing, also the ingredient 5 was added. The mixture was agitated for 10 minutes and then subjected to compression in a tabletting machine with punches of 15 x 6 mm (r = 5.0 mm) to make about 250 candle shaped tablets with double fracture line.
Samples were obtained having the following character-istics:
¦Example Average Weight Thickness Hardness Friability mg/tablet mm Kg 10 x 4 ~
1 505 5.33 13.4 0.20 2 455 ~.85 13.7 0.22 . _ .
Hardness of the tablets was determine~ with the apparatus Erweka TBH 28 and friability with the apparatus Roche Friabilator at 25 rpm checking the loss of weight of 10 tablets after 4 minutes of rotation.
In vitro release of the tablets was determined with the rotary paddle method described in USP, XXI ed., page 1244, employing according to the kind of analysis, the proper ~ ,~ "
-9- l ~
vessels containing 500 ml of arkificial gastric juice (pH
1.2) or 500 ml of artifical intestinal juice (pH 6.8) pre-heated at 37 C. The vessels were closed and agitator was regulated at a speed of 150 rpm. In each vessel a tablet corresponding to 350 mg of active substance was added.
At predetermined intervals of 1, 2, 4, 8, 12 and 14 hours a sample of 5 ml was taken and the vessel refilled with the same amount of juice or fluid. The sample was suikably diluted and analyzed at the spectrophotometer at a wavelength of 270 nm in 100 N HCl against standard reference.
The results of the analysis, given in the following table, show that the release of theophylline occurs in 12 or more hours according to the matrix composition.
Example Buffer p~ Cumulative release %
lh 2h 4h 8h 12h 14h 1.2 11.8 18.8 30.3 49.8 6l.4 66.3 6.8 9.1 15.7 2~.9 ~8.1 2 1.2 17.2 25.6 39.7 71.4 93.8 100.0 6.8 15.6 25.6 42.5 70.6 Theophylline tablets (dosage 350 mg) were prepared, in which the delaying substances are present in the amount given below:
Example ~o. Xanthan gum % Hydroxypropyl- Hydroxypropyl-methylcellulose % cellulose %
3 11.0 5.5 5.5 4 10 9lO.9 ___ ~' `: :
, -10- :L3~JJ~
Tablets of 350 mg each were prepared with the follow-ing excipients:
Excipients Example 4 Example 5 g mg/tablet g mg/tablet _ 1) Theophylline 105.0 350.0 105.0 350.0 . __ .
2) Xanthan gum 15.0 50.0 15.0 50.0 3) Hydroxypropyl-cellulose7.5 25.0 15.0 50.0 _ ._ .. _ ._ 4) Hydroxypropyl-methylcellulose 7.5 25.0 ________ 5) Fumed silica 0.6 2.0 0.62.0 ._ .... _ _ _.
6) ~agnesium stearate 1.5 3.0 1.55.0 Mixing was effected in the manner described in Examples 1-3. The mixture was subjected to compression in a tabletting machine with punches 15 x 6 mm tr = 5 mm) to make about 250 candle-shaped tablets with double fracture line.
The samples had the following characteristics:
Example Average Welght Thickness Hardness Friabillty No.mg/tablet mm Kg %
._ ..._ 3457 4.87 13.4 0.1 4457 4.85 13.7 0.1 Hardness and friability of the tablets were measured with the apparatus describerd in Examples 1-2.
In order to check the in vitro release, the same method used for Example 1-2 was employed and the results given in the following table were found, from which one can see the delayed release of the drug due to the xanthan gum based matrix.
`~, --ll--~ 3 ~
Example Buffer pH Cumulative releasë %
No. lh 2h 4h 8h 12h 14h 1.2 17. a 29.0 47.~ 80.2 95.9 6.8 12.6 23.2 38.7 58.8 79.7 1.2 15.3 25.1 40.5 65.5 88.7 100.0 6.8 12.3 21.0 34.2 55.1 81.4 100.0 Tablets of 50 mg of amitryptiline retard were pre-pared containing 16.6% of xanthan gum and 16.6 % of hydroxy-propylcellulose, as costituents of the delaying matrix.
The tablets of 50 mg were prepared with the following excipients:
Ingredients Example 5 g mg/tablet Amitryptiline 25 50.0 _ _ Xanthan gum10 20.0 -.. - .
Hydroxypropyl- 10 20.0 cellulose ........................... ...... ........ _ Lactose 13.75 27.5 _ _ .__ Fumed Silica 0.25 0.5 . ._ Magnesium stearate 1.00 2.0 Mixing was effected as in Examples 1-3. The mix-ture was subjected to compression in a tabletting machine with punches 4 x 9 mm to make about 350 flat candle tablets. The samples had the following characteristics:
._ Example No. Average Weight Hardness Frability mg/tablet Kg %
_ 120 7.06 0.1 .
-Hardness and friability of the tablets were measured with the apparatus describerd in Examples 1-2.
In order to check the in vitro release the same method used in Examples 1-2 was employed and the following results were obtained:
I _ _ Example ¦ Bu~fer pH Cumulative release %
No. ¦ _ lh 2h 4h 8h 1 1.2- 33.3148.8172.8l 100 Retard tablets of methoclopramide chlorohydrate were prepared with a dosage of 30 mg of methoclopramide, contain-ing either 29.2% xanthan gum, 14.6% hydroxypropylcellulose and 14.6 % hydroxypropylmethylcellulose (Ex. 6) or 31~9%
xanthan gum and 31.9% hydroxypropylmethylcellulose (Ex.7) as constituents o~ the delaying matrix. The tablets of 30 mg methoclopramide were prepared with the following excipients:
.._ Excipients Example 6 Example 7 g mg/tablet g mg/tablet 1) Methoclopramide HC1 16.8 33.7 16.8 33.7 _ ___ ~
2) Xanthun gum 17.5 35.0 17.5 35.0 __ ... ._ .. .
3) Hydroxypropyl-cellulose 8.717.5 .. _ _ 4) Hydroxypropyl-methylcellulose8.7 17.517.5 35.0 5) Spray Dry Lactose 5.110.3 . .
6) Fumed silica 1.0 2.0 1.0 2.0 _ 7) Magnesium stearate 2.04.0 2.0 4.0 _ ,, ~
-13- ~3~
Mixing was effected in the same manner as in Examples 1-2. The mixture was subjected to compression in a tablett-ing machine with punches 4 x 9 mm to make about 500 flat candle tablets having the following characteristics:
Example No. Average Weight Hardness Friability mg/tablet Kg %
_ . , 6 123 9.8 0.2 - .
_ 7 114 11.6 0.2 Hardness and friability of the tablets were measured with the apparatus described in Examples 1-2. In order to check -the in vitro release the same method of Examples 1-2 was used with the only change that the agitator was set at a speed of 125 rpm instead of 150 rpm.
The methoclopramide tablets had the ~ollowing in vitro release:
..
Example Buffer pH Cumulative release %
No. lh 2h 4h 8h 12h 16h _ 1.2 41.2 59.5 ~2.8 96.3 100.0 _ 6.8 35.2 49.1 68.7 82.0 91.3 97.6 . _ .
7 1.2 34.1 49.9 71.6 94.0 100.0 6.8 28.6 41.8 60.7 82.9 94.1 99.2 ,~3 ~ ,r, - 14 - ~ 3 ~
Mixing was effected in the same manner as in Examples 1-~. The mixture was subjected to compression in a tabletting machine with punches 4 x 9 mm to make about 5ûO flat candle tablets having the following characteristics:
Sample N Average weight Hardness Friability mg/tablet Kg O
Then ingredient 4 was added and after further 15 minutes of mixing, also the ingredient 5 was added. The mixture was agitated for 10 minutes and then subjected to compression in a tabletting machine with punches of 15 x 6 mm (r = 5.0 mm) to make about 250 candle shaped tablets with double fracture line.
Samples were obtained having the following character-istics:
¦Example Average Weight Thickness Hardness Friability mg/tablet mm Kg 10 x 4 ~
1 505 5.33 13.4 0.20 2 455 ~.85 13.7 0.22 . _ .
Hardness of the tablets was determine~ with the apparatus Erweka TBH 28 and friability with the apparatus Roche Friabilator at 25 rpm checking the loss of weight of 10 tablets after 4 minutes of rotation.
In vitro release of the tablets was determined with the rotary paddle method described in USP, XXI ed., page 1244, employing according to the kind of analysis, the proper ~ ,~ "
-9- l ~
vessels containing 500 ml of arkificial gastric juice (pH
1.2) or 500 ml of artifical intestinal juice (pH 6.8) pre-heated at 37 C. The vessels were closed and agitator was regulated at a speed of 150 rpm. In each vessel a tablet corresponding to 350 mg of active substance was added.
At predetermined intervals of 1, 2, 4, 8, 12 and 14 hours a sample of 5 ml was taken and the vessel refilled with the same amount of juice or fluid. The sample was suikably diluted and analyzed at the spectrophotometer at a wavelength of 270 nm in 100 N HCl against standard reference.
The results of the analysis, given in the following table, show that the release of theophylline occurs in 12 or more hours according to the matrix composition.
Example Buffer p~ Cumulative release %
lh 2h 4h 8h 12h 14h 1.2 11.8 18.8 30.3 49.8 6l.4 66.3 6.8 9.1 15.7 2~.9 ~8.1 2 1.2 17.2 25.6 39.7 71.4 93.8 100.0 6.8 15.6 25.6 42.5 70.6 Theophylline tablets (dosage 350 mg) were prepared, in which the delaying substances are present in the amount given below:
Example ~o. Xanthan gum % Hydroxypropyl- Hydroxypropyl-methylcellulose % cellulose %
3 11.0 5.5 5.5 4 10 9lO.9 ___ ~' `: :
, -10- :L3~JJ~
Tablets of 350 mg each were prepared with the follow-ing excipients:
Excipients Example 4 Example 5 g mg/tablet g mg/tablet _ 1) Theophylline 105.0 350.0 105.0 350.0 . __ .
2) Xanthan gum 15.0 50.0 15.0 50.0 3) Hydroxypropyl-cellulose7.5 25.0 15.0 50.0 _ ._ .. _ ._ 4) Hydroxypropyl-methylcellulose 7.5 25.0 ________ 5) Fumed silica 0.6 2.0 0.62.0 ._ .... _ _ _.
6) ~agnesium stearate 1.5 3.0 1.55.0 Mixing was effected in the manner described in Examples 1-3. The mixture was subjected to compression in a tabletting machine with punches 15 x 6 mm tr = 5 mm) to make about 250 candle-shaped tablets with double fracture line.
The samples had the following characteristics:
Example Average Welght Thickness Hardness Friabillty No.mg/tablet mm Kg %
._ ..._ 3457 4.87 13.4 0.1 4457 4.85 13.7 0.1 Hardness and friability of the tablets were measured with the apparatus describerd in Examples 1-2.
In order to check the in vitro release, the same method used for Example 1-2 was employed and the results given in the following table were found, from which one can see the delayed release of the drug due to the xanthan gum based matrix.
`~, --ll--~ 3 ~
Example Buffer pH Cumulative releasë %
No. lh 2h 4h 8h 12h 14h 1.2 17. a 29.0 47.~ 80.2 95.9 6.8 12.6 23.2 38.7 58.8 79.7 1.2 15.3 25.1 40.5 65.5 88.7 100.0 6.8 12.3 21.0 34.2 55.1 81.4 100.0 Tablets of 50 mg of amitryptiline retard were pre-pared containing 16.6% of xanthan gum and 16.6 % of hydroxy-propylcellulose, as costituents of the delaying matrix.
The tablets of 50 mg were prepared with the following excipients:
Ingredients Example 5 g mg/tablet Amitryptiline 25 50.0 _ _ Xanthan gum10 20.0 -.. - .
Hydroxypropyl- 10 20.0 cellulose ........................... ...... ........ _ Lactose 13.75 27.5 _ _ .__ Fumed Silica 0.25 0.5 . ._ Magnesium stearate 1.00 2.0 Mixing was effected as in Examples 1-3. The mix-ture was subjected to compression in a tabletting machine with punches 4 x 9 mm to make about 350 flat candle tablets. The samples had the following characteristics:
._ Example No. Average Weight Hardness Frability mg/tablet Kg %
_ 120 7.06 0.1 .
-Hardness and friability of the tablets were measured with the apparatus describerd in Examples 1-2.
In order to check the in vitro release the same method used in Examples 1-2 was employed and the following results were obtained:
I _ _ Example ¦ Bu~fer pH Cumulative release %
No. ¦ _ lh 2h 4h 8h 1 1.2- 33.3148.8172.8l 100 Retard tablets of methoclopramide chlorohydrate were prepared with a dosage of 30 mg of methoclopramide, contain-ing either 29.2% xanthan gum, 14.6% hydroxypropylcellulose and 14.6 % hydroxypropylmethylcellulose (Ex. 6) or 31~9%
xanthan gum and 31.9% hydroxypropylmethylcellulose (Ex.7) as constituents o~ the delaying matrix. The tablets of 30 mg methoclopramide were prepared with the following excipients:
.._ Excipients Example 6 Example 7 g mg/tablet g mg/tablet 1) Methoclopramide HC1 16.8 33.7 16.8 33.7 _ ___ ~
2) Xanthun gum 17.5 35.0 17.5 35.0 __ ... ._ .. .
3) Hydroxypropyl-cellulose 8.717.5 .. _ _ 4) Hydroxypropyl-methylcellulose8.7 17.517.5 35.0 5) Spray Dry Lactose 5.110.3 . .
6) Fumed silica 1.0 2.0 1.0 2.0 _ 7) Magnesium stearate 2.04.0 2.0 4.0 _ ,, ~
-13- ~3~
Mixing was effected in the same manner as in Examples 1-2. The mixture was subjected to compression in a tablett-ing machine with punches 4 x 9 mm to make about 500 flat candle tablets having the following characteristics:
Example No. Average Weight Hardness Friability mg/tablet Kg %
_ . , 6 123 9.8 0.2 - .
_ 7 114 11.6 0.2 Hardness and friability of the tablets were measured with the apparatus described in Examples 1-2. In order to check -the in vitro release the same method of Examples 1-2 was used with the only change that the agitator was set at a speed of 125 rpm instead of 150 rpm.
The methoclopramide tablets had the ~ollowing in vitro release:
..
Example Buffer pH Cumulative release %
No. lh 2h 4h 8h 12h 16h _ 1.2 41.2 59.5 ~2.8 96.3 100.0 _ 6.8 35.2 49.1 68.7 82.0 91.3 97.6 . _ .
7 1.2 34.1 49.9 71.6 94.0 100.0 6.8 28.6 41.8 60.7 82.9 94.1 99.2 ,~3 ~ ,r, - 14 - ~ 3 ~
Mixing was effected in the same manner as in Examples 1-~. The mixture was subjected to compression in a tabletting machine with punches 4 x 9 mm to make about 5ûO flat candle tablets having the following characteristics:
Sample N Average weight Hardness Friability mg/tablet Kg O
8 123 9.8 0.2 9 114 11.6 0.2 Hardness and friability of the tablets were measured with the apparatus described in Examples 1-3. In order to check the in vitro release the same method of Examples 1-3 was used with the only change that the agitator was set at a speed of 125 rpm instead of 150 rpm.
The methoclopramide tablets had the following in vitro release:
Sample Buffer pH Cumulative release O
lh 2h 4h- Bh 12h 16h 8 1.2 41~2 59.5 82.8 96,3 100~0 6.8 35,2 49~1 6B~7 82~0 91.3 97.6 9 1.2 34,1 49~ 9 71~6 94O0 100.. 0 6~8 28i,6 41.8 60.7 82.9 94tl 99.2 -Retard tablets of methoclopramide chlorohydrate of 30 mg methoclo-20 pramide were prepared, containing 58.6 % xanthan gum as a delaying substance.
The 3û mg methoclopramide tablets were prepared with the following excipients:
- 15 - 1 3 ~
lngredients Esempio 10 g mg/ tab I e t Methoc1Opramide HC1 16.8 33.7 Xanthan gum 35.1 70.3 Spray Dry Lactose 5.0 10.0 Flame silica 1.0 2.0 Magnesium stearate 2.0 4.0 .__ ._ . .. _ :
Mixing was effected in the same manner as in Examples 1-3. The rnixture was subjected to compression in a tabletting machine with punches 4 x 9 mm to make about 500 flat candle tablets having the following characteristics:
Sample N Averaye weight Hardness Friability mg/tablet Kg O
_ ~
126.4 7.7 0.2 Hardness and friability of the tablets were rneasured with the apparatus 15 described in Examples 1-30 In order to check the in vitro release the same method used for Examples 8 and 9 was employed. The tablets had the following in vitro release:
Sample N Buffer pH Cumulative release O
lh 2h 4h 8h 12h 16h -- . . .
1.2 43. ~ 61.5 E34.0 100 6.8 27.8 41.8 61.6 85.4 93.5 98.6 Retard tablets of theophylline with a dosage of 350 mg were prepared, containing 25 the percentages of delaying substances indicated in the following table:
Example NInstallt Cleargel ~uHydIoxypropylce:lluloae 11 26.9 9.0 12 19.7 9.0 13 10.9 10.9 The tablets of 350 mg were prepared with the following excipients:
Ingredients Example 11 Example 12 [xarnple 13 ymg/tablet g mg/tablet g mg/ tablet Theophylline 105 350 105 350 105 350 Instant Cleargel45 150 30 100 15 50 Hyd,roxypl~Opyl-cellulose LF 1550 15 50 Hydroxypropyl-cellulose HF ____ -- -- 15 50 Flame silica 0.6 2 0~6 2 0~6 2 Magnesium stearate 1.5 5 1.5 5 . 1~5 S
15 was compressed in a tabletting machine with punches 15 x 6 mm tr - 5 rnm) to make about 250 candle shaped tablets with double fracture line. The samples had the following characteristics:
Sample NAverage weight ThicknessHardness Friability mg/tablet mm Kg Do .........._._.. _~_ ._.. _ _ . .~ j 11 557 5 . 00 13 . 1 0 . 1 12 507 5.56 13.7 0.1 13 457 5.12 15.6 0.1 ,.
Hardness and friability of the tablets were measured with the apparatus described in Examples 1-3.
In order to check the in vitro release the same method used for Examples 1-~5 3 was employed and the results are given in the following table, where one can see !
.
. , .
.
- 17 - L3~L6~ ~
the delaying effect of drug release due to the matrix based on Instant Cleargel Sample Na Buf~er pH Cumulative release O
lh 2h 4h 8h 12h 14h 11 1,2 20.2 38.1 ~0 3 8~,2 12 1,2 2B.3 45.1 fi8.5 88.1 .. . ...
131,2 28,1 35.4 48.7 71,g 87.0 93,5 6.8 31 2 37,9 ~l9.6 70.0 84,7 ~1.5 TheDphylline tablets with a dosage of 350 mg were prepared, containing as 10 delaying substance 22% of Instant Cleargel . The tablets had the fo~lowing composition:
Ingredients Example 14 9 mg/ tablet Theophylline 105 ~50 15 Instant Clearqel 30 100 Flame silica 0.6 2 Magnesium Stearate 1.5 5 Mixing was effected as in Examples 1-3. The mixture was subjected to compression in a tabletting machine with punches 15 x 6 mm (r = 5 mm) to make about 250 candle-shaped tablets with double fracture line having the following 20 characteristics:
Sample N Average weight Thickness Hardness Friability ma/tablet mm Ka Do 14 457 5.0~ 14.1 0.1 and the following in vitro release:
Sample N Buffer pH Cumulative release O
lh 2h 4h 8h 14 1.2 28.1 35.4 48.7 71.9 - 1~ 13~ 8 .
Hard gelatin capsule (size 1, transparent neutral colour) of theophylline (dosage 100 mg) were prepared, containing as delaying substance 33.3 % of xanthan gum with the following composition:
Ingredients Example 15 g mg/tablet Theophylline 30 100 Xanthan gum 60 200 .
The mixture was prepared as in the Examples 1-3.
The capsules were filled with a laboratory capsule filling maclline of the Zuma type in order to make 3ûû capsules.
For controlli-~g the in vitro release the same method used for Exarnples 1-3 was employed, with the only variant that the agitator was set at a speed of 75 rpm instead 150 rpm.
The theophylline release from the capsules is delayed by the Xanthan gum 15 matrix as shown by the following values of in vitro release:
Sample ND Buffer pH Cumulative release O
lh 2h 4h 8h 1.2 21.2 36.3 60.1 83.0 It is therefore clear, from the foregoing description and the illustrative 20 examples, that the desired objects are fully attained, while it is also to beunderstood that many variations, modifications, additions and/or substitutions of ele,-nents may be resorted to the formulations according to the present invention, without departing however from its spirit and objects and without fallirlg outside its scope of protection, as it is defined in the appended claims.
. . .
The methoclopramide tablets had the following in vitro release:
Sample Buffer pH Cumulative release O
lh 2h 4h- Bh 12h 16h 8 1.2 41~2 59.5 82.8 96,3 100~0 6.8 35,2 49~1 6B~7 82~0 91.3 97.6 9 1.2 34,1 49~ 9 71~6 94O0 100.. 0 6~8 28i,6 41.8 60.7 82.9 94tl 99.2 -Retard tablets of methoclopramide chlorohydrate of 30 mg methoclo-20 pramide were prepared, containing 58.6 % xanthan gum as a delaying substance.
The 3û mg methoclopramide tablets were prepared with the following excipients:
- 15 - 1 3 ~
lngredients Esempio 10 g mg/ tab I e t Methoc1Opramide HC1 16.8 33.7 Xanthan gum 35.1 70.3 Spray Dry Lactose 5.0 10.0 Flame silica 1.0 2.0 Magnesium stearate 2.0 4.0 .__ ._ . .. _ :
Mixing was effected in the same manner as in Examples 1-3. The rnixture was subjected to compression in a tabletting machine with punches 4 x 9 mm to make about 500 flat candle tablets having the following characteristics:
Sample N Averaye weight Hardness Friability mg/tablet Kg O
_ ~
126.4 7.7 0.2 Hardness and friability of the tablets were rneasured with the apparatus 15 described in Examples 1-30 In order to check the in vitro release the same method used for Examples 8 and 9 was employed. The tablets had the following in vitro release:
Sample N Buffer pH Cumulative release O
lh 2h 4h 8h 12h 16h -- . . .
1.2 43. ~ 61.5 E34.0 100 6.8 27.8 41.8 61.6 85.4 93.5 98.6 Retard tablets of theophylline with a dosage of 350 mg were prepared, containing 25 the percentages of delaying substances indicated in the following table:
Example NInstallt Cleargel ~uHydIoxypropylce:lluloae 11 26.9 9.0 12 19.7 9.0 13 10.9 10.9 The tablets of 350 mg were prepared with the following excipients:
Ingredients Example 11 Example 12 [xarnple 13 ymg/tablet g mg/tablet g mg/ tablet Theophylline 105 350 105 350 105 350 Instant Cleargel45 150 30 100 15 50 Hyd,roxypl~Opyl-cellulose LF 1550 15 50 Hydroxypropyl-cellulose HF ____ -- -- 15 50 Flame silica 0.6 2 0~6 2 0~6 2 Magnesium stearate 1.5 5 1.5 5 . 1~5 S
15 was compressed in a tabletting machine with punches 15 x 6 mm tr - 5 rnm) to make about 250 candle shaped tablets with double fracture line. The samples had the following characteristics:
Sample NAverage weight ThicknessHardness Friability mg/tablet mm Kg Do .........._._.. _~_ ._.. _ _ . .~ j 11 557 5 . 00 13 . 1 0 . 1 12 507 5.56 13.7 0.1 13 457 5.12 15.6 0.1 ,.
Hardness and friability of the tablets were measured with the apparatus described in Examples 1-3.
In order to check the in vitro release the same method used for Examples 1-~5 3 was employed and the results are given in the following table, where one can see !
.
. , .
.
- 17 - L3~L6~ ~
the delaying effect of drug release due to the matrix based on Instant Cleargel Sample Na Buf~er pH Cumulative release O
lh 2h 4h 8h 12h 14h 11 1,2 20.2 38.1 ~0 3 8~,2 12 1,2 2B.3 45.1 fi8.5 88.1 .. . ...
131,2 28,1 35.4 48.7 71,g 87.0 93,5 6.8 31 2 37,9 ~l9.6 70.0 84,7 ~1.5 TheDphylline tablets with a dosage of 350 mg were prepared, containing as 10 delaying substance 22% of Instant Cleargel . The tablets had the fo~lowing composition:
Ingredients Example 14 9 mg/ tablet Theophylline 105 ~50 15 Instant Clearqel 30 100 Flame silica 0.6 2 Magnesium Stearate 1.5 5 Mixing was effected as in Examples 1-3. The mixture was subjected to compression in a tabletting machine with punches 15 x 6 mm (r = 5 mm) to make about 250 candle-shaped tablets with double fracture line having the following 20 characteristics:
Sample N Average weight Thickness Hardness Friability ma/tablet mm Ka Do 14 457 5.0~ 14.1 0.1 and the following in vitro release:
Sample N Buffer pH Cumulative release O
lh 2h 4h 8h 14 1.2 28.1 35.4 48.7 71.9 - 1~ 13~ 8 .
Hard gelatin capsule (size 1, transparent neutral colour) of theophylline (dosage 100 mg) were prepared, containing as delaying substance 33.3 % of xanthan gum with the following composition:
Ingredients Example 15 g mg/tablet Theophylline 30 100 Xanthan gum 60 200 .
The mixture was prepared as in the Examples 1-3.
The capsules were filled with a laboratory capsule filling maclline of the Zuma type in order to make 3ûû capsules.
For controlli-~g the in vitro release the same method used for Exarnples 1-3 was employed, with the only variant that the agitator was set at a speed of 75 rpm instead 150 rpm.
The theophylline release from the capsules is delayed by the Xanthan gum 15 matrix as shown by the following values of in vitro release:
Sample ND Buffer pH Cumulative release O
lh 2h 4h 8h 1.2 21.2 36.3 60.1 83.0 It is therefore clear, from the foregoing description and the illustrative 20 examples, that the desired objects are fully attained, while it is also to beunderstood that many variations, modifications, additions and/or substitutions of ele,-nents may be resorted to the formulations according to the present invention, without departing however from its spirit and objects and without fallirlg outside its scope of protection, as it is defined in the appended claims.
. . .
Claims (4)
1. Formulation for preparing solid dosage forms having a regular and sustained release, comprising one or more active substances and a matrix characterized in that the percentage by weight of the matrix components is above 50% but below 75%
of xanthan gum and up to 50% of one or more of the following polymers: methylcellulose, hydroxyethylcellulose, hydroxypro-pylcellulose, hydroxypropylmethylcellulose.
of xanthan gum and up to 50% of one or more of the following polymers: methylcellulose, hydroxyethylcellulose, hydroxypro-pylcellulose, hydroxypropylmethylcellulose.
2. Formulation according to Claim 1, when used for the preparation of sustained release pharmaceutical solid dosage forms, including tablets, capsules, lozenges and the like.
3. Formulation according to Claim 1 wherein, in addition to one or more active substances and the constituents of the delaying matrix, there are inert excipients used for obtain-ing the desired dosage form, including lubricants, dyestuffs, diluents, sweeteners, flavouring agents.
4. Formulation according to Claim 1, Claim 2 or Claim 3, characterized in that the release of said one or more active substances is prolonged up to 24 hours so as to allow one single administration per day.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT19675A/86 | 1986-03-07 | ||
| IT19675/86A IT1191674B (en) | 1986-03-07 | 1986-03-07 | FORMULATIONS FOR THE PREPARATION OF PROLONGED-RELEASE DRUGS SUITABLE FOR ORAL ADMINISTRATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1316108C true CA1316108C (en) | 1993-04-13 |
Family
ID=11160299
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000531406A Expired - Fee Related CA1316108C (en) | 1986-03-07 | 1987-03-06 | Formulation for preparing sustained release drugs for oral administration |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US5047248A (en) |
| EP (1) | EP0261213B1 (en) |
| JP (1) | JP2617109B2 (en) |
| KR (1) | KR880701099A (en) |
| CA (1) | CA1316108C (en) |
| DK (1) | DK172117B1 (en) |
| HK (1) | HK12395A (en) |
| IT (1) | IT1191674B (en) |
| NZ (1) | NZ219523A (en) |
| PT (1) | PT84416B (en) |
| WO (1) | WO1987005212A1 (en) |
| ZA (1) | ZA871620B (en) |
Families Citing this family (54)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8601204D0 (en) * | 1986-01-18 | 1986-02-19 | Boots Co Plc | Therapeutic agents |
| US4994276A (en) * | 1988-09-19 | 1991-02-19 | Edward Mendell Co., Inc. | Directly compressible sustained release excipient |
| US5096714A (en) * | 1988-06-28 | 1992-03-17 | Hauser-Kuhrts, Inc. | Prolonged release drug tablet formulations |
| US5128143A (en) * | 1988-09-19 | 1992-07-07 | Edward Mendell Co., Inc. | Sustained release excipient and tablet formulation |
| US5169639A (en) * | 1988-09-19 | 1992-12-08 | Edward Mendell Co., Inc. | Controlled release verapamil tablets |
| US5032406A (en) * | 1989-02-21 | 1991-07-16 | Norwich Eaton Pharmaceuticals, Inc. | Dual-action tablet |
| US5478577A (en) * | 1993-11-23 | 1995-12-26 | Euroceltique, S.A. | Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level |
| US5292534A (en) * | 1992-03-25 | 1994-03-08 | Valentine Enterprises, Inc. | Sustained release composition and method utilizing xanthan gum and an active ingredient |
| US5298261A (en) * | 1992-04-20 | 1994-03-29 | Oregon Freeze Dry, Inc. | Rapidly distintegrating tablet |
| NL9201195A (en) * | 1992-07-03 | 1994-02-01 | Tno | PREPARATION FOR THE REGULATED DELIVERY OF AN ACTIVE SUBSTANCE AND METHOD FOR PREPARING SUCH A PREPARATION. |
| US5472711A (en) * | 1992-07-30 | 1995-12-05 | Edward Mendell Co., Inc. | Agglomerated hydrophilic complexes with multi-phasic release characteristics |
| US5399354A (en) * | 1993-05-28 | 1995-03-21 | Mcneil-Ppc, Inc. | Process for making a hard-candy based oral pharmaceutical lozenge containing an antacid |
| US5993860A (en) * | 1993-06-17 | 1999-11-30 | Venture Lending | NSADI delivery employing a powdered hydrocolloid gum obtainable from higher plants |
| US6676967B1 (en) | 1993-09-20 | 2004-01-13 | Kos Pharmaceuticals, Inc. | Methods for reducing flushing in individuals being treated with nicotinic acid for hyperlipidemia |
| US6818229B1 (en) | 1993-09-20 | 2004-11-16 | Kos Pharmaceuticals, Inc. | Intermediate release nicotinic acid compositions for treating hyperlipidemia |
| US6746691B2 (en) | 1993-09-20 | 2004-06-08 | Kos Pharmaceuticals, Inc. | Intermediate release nicotinic acid compositions for treating hyperlipidemia having unique biopharmaceutical characteristics |
| US6080428A (en) | 1993-09-20 | 2000-06-27 | Bova; David J. | Nicotinic acid compositions 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 |
| FR2729857B1 (en) | 1995-01-27 | 1997-04-04 | Rhone Poulenc Chimie | PHARMACEUTICAL COMPOSITIONS IN THE FORM OF SUSTAINED-RELEASE TABLETS BASED ON GRANULES OF HIGH MOLECULAR POLYSACCHARIDES |
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-
1986
- 1986-03-07 IT IT19675/86A patent/IT1191674B/en active
-
1987
- 1987-03-02 JP JP62502489A patent/JP2617109B2/en not_active Expired - Fee Related
- 1987-03-02 EP EP87902464A patent/EP0261213B1/en not_active Expired - Lifetime
- 1987-03-02 KR KR1019870701020A patent/KR880701099A/en not_active Application Discontinuation
- 1987-03-02 WO PCT/EP1987/000124 patent/WO1987005212A1/en active IP Right Grant
- 1987-03-05 NZ NZ219523A patent/NZ219523A/en unknown
- 1987-03-06 PT PT84416A patent/PT84416B/en not_active IP Right Cessation
- 1987-03-06 CA CA000531406A patent/CA1316108C/en not_active Expired - Fee Related
- 1987-03-06 ZA ZA871620A patent/ZA871620B/en unknown
- 1987-11-05 DK DK582287A patent/DK172117B1/en not_active IP Right Cessation
-
1989
- 1989-02-08 US US07/308,120 patent/US5047248A/en not_active Expired - Fee Related
-
1995
- 1995-01-26 HK HK12395A patent/HK12395A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK582287D0 (en) | 1987-11-05 |
| PT84416B (en) | 1989-10-04 |
| NZ219523A (en) | 1990-08-28 |
| PT84416A (en) | 1987-04-01 |
| WO1987005212A1 (en) | 1987-09-11 |
| ZA871620B (en) | 1988-02-24 |
| HK12395A (en) | 1995-02-03 |
| AU7288387A (en) | 1987-09-28 |
| EP0261213A1 (en) | 1988-03-30 |
| DK582287A (en) | 1987-11-05 |
| IT1191674B (en) | 1988-03-23 |
| IT8619675A1 (en) | 1987-09-07 |
| US5047248A (en) | 1991-09-10 |
| KR880701099A (en) | 1988-07-25 |
| DK172117B1 (en) | 1997-11-17 |
| JP2617109B2 (en) | 1997-06-04 |
| IT8619675A0 (en) | 1986-03-07 |
| EP0261213B1 (en) | 1992-08-05 |
| JPS63503225A (en) | 1988-11-24 |
| AU603098B2 (en) | 1990-11-08 |
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