EP1231896A1 - Compositions orales a gout masque - Google Patents
Compositions orales a gout masqueInfo
- Publication number
- EP1231896A1 EP1231896A1 EP00973153A EP00973153A EP1231896A1 EP 1231896 A1 EP1231896 A1 EP 1231896A1 EP 00973153 A EP00973153 A EP 00973153A EP 00973153 A EP00973153 A EP 00973153A EP 1231896 A1 EP1231896 A1 EP 1231896A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- granulation
- weight
- methacrylic acid
- acid ester
- taste
- 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.)
- Withdrawn
Links
Definitions
- the present invention relates to a granulation of a pharmaceutically active ingredient with an aqueous solution comprising a neutral methacrylic acid ester copolymer and a binder for the purpose of masking the taste of the pharmaceutically active ingredient.
- drugs are preferentially formulated as oral dosage forms due to the ease of administration and low cost of development.
- drugs are formulated as chewable or dispersible tablets, as dry powder for reconstitution or as liquid oral dosage forms. These formulations allow a greater exposure of the drug to the taste buds resulting in problems of patient compliance when highly bitter or unpleasant tasting drugs have to be administered.
- Microencapsulation of drug particles is a technology intenstive technique, requiring both sophistication in equipment and prior expertise of fine particle encapsulation.
- Numerous prior art documents disclose techniques of solvent based desolvation, interfacial condensation or denaturation, or particle coating in fluid bed coaters selecting any of the film formers from the short list of polymers commercially available. Again, the presence of organic solvents may generate regulatory and safety issues, particularly with respect to pediatric patients.
- Lipid entrapment often requires the use of spray congealing technique, which is quite sophisticated. Besides, for thermo-sensitive drugs, suspension in molten lipid during processing, may cause extensive drug degradation.
- Another taste masking technique which has been employed involves granulation of the bitter drug with polymers such that significant taste masking can be achieved.
- the granulated product may optionally be coated for achieving complete taste masking.
- Examples of this technique include that described in U.S. Patent No. 4,101 ,651.
- This patent describes a process for taste masking of bitter drugs for oral administration. The process involves dissolving ethyl cellulose at high concentration and adding the bitter drug, midecamycin into the solution. The midecamycin - ethyl cellulose suspension is kneaded followed by the addition of silicic acid anhydride to form a powder and granulating the powder using a solution of bitter taste masking substance in a fluidized bed granulator. Up to three times ethylcellulose by weight of the drug is used for taste masking. Apart from the use of large amounts of polymer, this method also suffers from the disadvantage of using organic solvents for granulation.
- U.S. Patent No. 4,916,161 describes a process for preparing taste masked tablets containing a foul tasting pharmaceutical agent, by wet granulating a dry particulate pre-granulation blend comprising the pharmaceutical active and hydroxypropyl methylcellulose phthalate with an aqueous granulating composition comprising a solution in which hydroxypropyl methyl- cellulose phthalate is at least partially soluble.
- This patent describes the use of an enteric polymer for taste masking and would be useful only when the drug is intended to be released in the distal portion of the gastrointestinal tract.
- U.S. Patent No. 5,188,839 describes a taste masked chewable tablet composition of cimetidine which comprises an effective amount of cimetidine and about 2-20% w/w relative to cimetidine of a copolymer of dimethyl ethyl methacrylate and neutral methacrylic acid esters (sold under the tradename of
- U.S. Patent No. 5,047,319 describes a pharmaceutical granule composition comprising cimetidine and a taste masking and granulating agent, an ester of a polyhydroxy compound, wherein the polyhydroxy compound is a non-polymeric, non-aromatic hydrocarbon or carbohydrate having at least 2 hydroxyl groups per molecule.
- compositions described so far generally require the use of large amount of polymers or waxes for effective taste-masking and use of organic solvents for granulation. Accordingly, none of the taste masking techniques heretofore described is completely satisfactory.
- the object of the present invention is to provide a process for taste masking of bitter drugs, wherein the drug is granulated with small to moderate amounts of a polymer without the use of any organic solvent. It gives obvious benefits with respect to cost effectiveness and environment friendly operations. It is also among the simplest of techniques for taste masking and is suitable for a wide range of very bitter drugs.
- a taste masking formulation is described, wherein a pharmaceutically active ingredient is granulated with an aqueous solution comprising a neutral methacrylic acid ester copolymer and a binder, the resulting granules being optionally coated.
- the granules so prepared have an acceptable taste and have good dissolution characteristic in the simulated gastro-intestinal media.
- Polymer suitable for use in the present invention is a neutral copolymer of ethyl acrylate and methyl methacrylate also known as neutral methacrylic
- Said polymer is a compound of Formula I:
- R is — COO.CH 3 .
- small to moderate amounts of the polymer composition is sufficient to mask the bitter taste of the drug.
- the dry weight of the co-polymer should be between 5-30% by weight of the pharmaceutical active and, more preferably, between 8-25% by weight of the pharmaceutical
- the granules of the present invention are typically prepared by wet granulation method wherein an aqueous dispersion of the neutral methacrylic acid ester copolymer along with a binder is added to the powdered pharmaceutical ingredient, optionally mixed with other pharmaceutically acceptable excipients such as glidants and anti-adhesives and the resulting mixture is blended to form granules.
- aqueous dispersion of the neutral methacrylic acid ester copolymer along with a binder is added to the powdered pharmaceutical ingredient, optionally mixed with other pharmaceutically acceptable excipients such as glidants and anti-adhesives and the resulting mixture is blended to form granules.
- the use of polymer dispersion alone as the granulating fluid creates problems during drying at elevated temperatures due to polymer softening. This problem has been overcome by the addition of a binder together with the polymer which gives additional hardness to the granules and facilitates the process of drying. It
- Binder is selected from those used conventionally such as starch, acacia, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl methylcellu- lose, hydroxypropyl cellulose, carboxymethyl cellulose, and hydroxyethyl cellulose. More preferably, the binder is chosen from amongst the commonly available carbohydrates such as sucrose, fructose and lactose. Most preferably, the binder employed is sucrose. The polymer and the binder are present in the ratio of 0.9: 0.1 to 0.1 :0.9 and more preferably, in the ratio of
- Glidants/anti-adhesives are the agents, which are used to decrease or to avoid adhesion or the agglutination of particles during the coating process.
- Suitable substances are, for example, magnesium stearate, calcium stearate, calcium behenate, talc, colloidal silicic acid, stearic acid, precirol (mixture of moni-, di-, and triesters of palmitic and stearic acid with glycerol), hydrogenated cottonseed oil, hydrogenated ester oil and polyethylene glycol of differing molecular weights.
- Amounts of 0.1-150%, particularly of 5-100% by weight of the neutral methacrylic acid ester copolymer are preferably employed.
- the granules so obtained may optionally be coated for additional taste- masking of the product.
- Polymers conventionally used for coating include, the cellulosic polymers, vinyl polymers, polymethacrylate copolymers and enteric polymers.
- Film forming polymers which are useful may include alkyl celluloses, such as, methyl or ethyl cellulose, hydroxyalkylcelluloses, such as hydroxypropyl cellulose or hydroxypropyl methylcellulose, vinyl polymers, such as polyvinyl acetate or polyvinyl acetate phthalate, polymethacrylate
- the coating polymer applied may be 1 to 50%, more preferably, 1 to 20% and most preferably, 3 to 15% by weight of the core.
- the granules so prepared when ingested, release the incorporated medicinal actives slowly enough to avoid the perception of bitterness in the mouth, and thus allow the preparation of suitable unit dosage forms for oral administration.
- the new particles are particularly suited for processing to give chewable and dispersible tablets, granules for reconstitution, non-aqueous oily suspension, capsules, sprinkles and the like.
- the particles employed for above applications is about 50 microns to 1000 microns and average size of the particles about 250 microns.
- Powder blend formula for granulation
- Granulating liquid was prepared by mixing the sugar with the polymer dispersion under stirring and diluting the same with the required amount of water.
- the granulating liquid so prepared was added to the drug powder blend and granulated.
- the granules were then dried at 60°C. Dried granules were sifted to give BSS#44/100 size fraction.
- the granules so prepared had good taste and desired release profile.
- Granulating liquid was prepared by dissolving Pharma Sugar into sufficient quantity of purified water and subsequently mixing it with polymer dispersion with continuous stirring. Resultant mixture was then mixed with the remaining amount of water and used after screening through BSS#85. Norfloxacin powder was mixed with Aerosil ® 200 (sifted through BSS
- the dry powder blend was granulated with the prepared granulating liquid as described in Example 2, and the granules were dried at 60°C. The granules when evaluated for taste did not give any bitterness in the mouth. Dried and sized granules (BSS #44/100) were lubricated with 0.5% colloidal silicon dioxide and taste masking was further optimized by coating.
- 100g of the granules were coated with the coating composition as described in Table 3.3.
- the amount of methyacrylic acid copolymer applied was 10% by weight of the core.
- the coating was carried out in Glatt GPCG-1 equipment with a bed temperature not exceeding 32°C, fluidizing air velocity less than 2 m/sec and an atomization pressure of 2 bars.
- the resultant granules had improved taste and were suitable for dispersion in suspension base.
- Powder blend formula for granulation
- Granulating liquid was prepared by mixing the sugar with polymer dispersion under stirring for 30 minutes.
- the granulating liquid so prepared was added to the drug powder blend and granulated.
- the granules were then dried at 60°C. Dried granules were sifted to give BSS #25/60 size fraction.
- the granules so prepared had about 75% drug loading and had improved taste.
- 100g of the granules were coated with the coating composition as described in Table 3.3.
- the coating was carried out in Glatt GPCG-1 equipment with a bed temperature not exceeding 32°C, fluidizing air velocity less than 2m/sec and an atomization pressure of 2 bars.
- Granulating liquid was prepared as described in Example 2. Dry powdered ingredients were sifted through BSS #60 and blended in a double cone blender for 20 minutes. Blended powder was granulated with the prepared granulating liquid and granules so obtained were dried at 60°C, followed by sizing to give BSS #44/100 fraction. The granules gave no bitter taste when kept in the mouth.
- EXAMPLE 6 Table 6.1
- Powder blend formula for granulation
- Granulating liquid was prepared by mixing the sugar with polymer dispersion under stirring for 30 minutes.
- the dry powder blend was mixed and sifted through BSS #60.
- Blended powder was granulated with the prepared granulating liquid and granules so obtained were dried at 60°C, followed by sizing to give BSS
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne le masquage efficace du goût d'un ingrédient pharmaceutiquement par granulation dudit ingrédient à l'aide d'une solution aqueuse comprenant un copolymère d'ester d'acide méthacrylique neutre et un liant.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
INDE148299 | 1999-11-16 | ||
IN1482DE1999 IN191043B (fr) | 1999-11-16 | 1999-11-16 | |
PCT/IB2000/001675 WO2001035930A1 (fr) | 1999-11-16 | 2000-11-15 | Compositions orales a gout masque |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1231896A1 true EP1231896A1 (fr) | 2002-08-21 |
EP1231896A4 EP1231896A4 (fr) | 2003-07-09 |
Family
ID=56290081
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP00973153A Withdrawn EP1231896A4 (fr) | 1999-11-16 | 2000-11-15 | Compositions orales a gout masque |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP1231896A4 (fr) |
AU (1) | AU1169601A (fr) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0136103A2 (fr) * | 1983-08-31 | 1985-04-03 | Yamanouchi Pharmaceutical Co. Ltd. | Formulations à action prolongée du chlorohydrate d'amosulalol |
DE3943242A1 (de) * | 1988-12-23 | 1990-06-28 | Poli Ind Chimica Spa | Vollstaendiger oder partieller ueberzug von pharmazeutischen wirkstoffen und entsprechende zusammensetzungen |
EP0526862A1 (fr) * | 1991-08-06 | 1993-02-10 | VECTORPHARMA INTERNATIONAL S.p.A. | Compositions pharmaceutiques solides pour l'administration orale à séjour gastrique prolongé |
US5198226A (en) * | 1986-01-30 | 1993-03-30 | Syntex (U.S.A.) Inc. | Long acting nicardipine hydrochloride formulation |
WO1999017742A2 (fr) * | 1997-10-03 | 1999-04-15 | Elan Corporation, Plc | Preparation au gout dissimule |
US5919489A (en) * | 1995-11-01 | 1999-07-06 | Abbott Laboratories | Process for aqueous granulation of clarithromycin |
-
2000
- 2000-11-15 AU AU11696/01A patent/AU1169601A/en not_active Abandoned
- 2000-11-15 EP EP00973153A patent/EP1231896A4/fr not_active Withdrawn
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0136103A2 (fr) * | 1983-08-31 | 1985-04-03 | Yamanouchi Pharmaceutical Co. Ltd. | Formulations à action prolongée du chlorohydrate d'amosulalol |
US5198226A (en) * | 1986-01-30 | 1993-03-30 | Syntex (U.S.A.) Inc. | Long acting nicardipine hydrochloride formulation |
DE3943242A1 (de) * | 1988-12-23 | 1990-06-28 | Poli Ind Chimica Spa | Vollstaendiger oder partieller ueberzug von pharmazeutischen wirkstoffen und entsprechende zusammensetzungen |
EP0526862A1 (fr) * | 1991-08-06 | 1993-02-10 | VECTORPHARMA INTERNATIONAL S.p.A. | Compositions pharmaceutiques solides pour l'administration orale à séjour gastrique prolongé |
US5919489A (en) * | 1995-11-01 | 1999-07-06 | Abbott Laboratories | Process for aqueous granulation of clarithromycin |
WO1999017742A2 (fr) * | 1997-10-03 | 1999-04-15 | Elan Corporation, Plc | Preparation au gout dissimule |
Non-Patent Citations (1)
Title |
---|
See also references of WO0135930A1 * |
Also Published As
Publication number | Publication date |
---|---|
EP1231896A4 (fr) | 2003-07-09 |
AU1169601A (en) | 2001-05-30 |
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