IE990009A1 - Taste-masked composition - Google Patents
Taste-masked compositionInfo
- Publication number
- IE990009A1 IE990009A1 IE990009A IE990009A IE990009A1 IE 990009 A1 IE990009 A1 IE 990009A1 IE 990009 A IE990009 A IE 990009A IE 990009 A IE990009 A IE 990009A IE 990009 A1 IE990009 A1 IE 990009A1
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- IE
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- taste
- drug
- resin
- masked composition
- exchange resin
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A taste-masked pharmaceutical composition containing a drug which is bound/adsorbed to an ion-exchange resin and subsequently coated with a polymeric material. Compositions of the invention are particularly advantageous for formulating drug compounds which have particularly strong and unpleasant strong and unpleasant tastes or odours. Oral dosage forms comprising taste masked compositions are also provided.
Description
A taste-masked pharmaceutical composition containing a drug which is bound/adsorbed to an ion-exchange resin and subsequently coated with a polymeric material. Compositions of the invention are particularly advantageous for formulating drug compounds which have particularly strong and unpleasant strong and unpleasant tastes or odours. Oral dosage forms comprising taste masked compositions are also provided.
The present invention relates to a taste masked composition. In particular, the invention 5 relates to a taste-masked pharmaceutical composition containing a drug which is loaded onto an ion-exchange resin and subsequently coated.
Oral administration represents the preferred route of administration for a wide range of pharmaceutical agents. Particular advantages associated with oral administration include ease of administration and convenience for the patient, both of which can lead to improved patient compliance. However, some drugs have an inherently bitter or unpalatable taste associated with them. This is a distinct problem if it is desirable to formulate these drugs in an oral dosage form. Various methods have been developed for masking the taste of such drugs so as to facilitate their formulation for oral administration.
For example, it is known that adsorption of a bitter tasting drug on to an ion-exchange resin may improve the taste characteristic of the drug. US 5,032,393 (Glaxo Group Ltd.) teaches that the bitter taste of ranitidine may be masked by forming an adsorbate with a synthetic cation exchange resin. The absorbate may then be incorporated into compositions for oral administration. Specifically, the synthetic cation exchange resin is selected from copolymers of styrene and divinylbenzene which are sulphonated, and copolymers of methacrylic acid and divinylbenzene. US 5,188,825 (lies et al.) discloses a freeze-dried dosage form comprising a water soluble active agent which is bonded to an ion-exchange resin to form a substantially water insoluble complex. The dosage form is prepared by mixing the water insoluble complex with a compatible carrier and freeze-drying the mixture. It is taught that these freeze-dried dosage forms reduce the undesirable odour and / or taste of active agents. Chlorpheniramine maleate and phenylephrine hydrochloride compositions are given as examples.
However, it is apparent that in the case of particularly bitter or unpleasant tasting drugs the use of such drug / resin complexes or absorbates, as described above in relation to
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the prior art, is not sufficient to eliminate the undesirable taste. Additionally, some ionexchange resin materials themselves have unpleasant taste characteristics adding to, rather than reducing, the problems of formulating organoleptically acceptable oral dosage forms.
Therefore, a need exists for a taste-masked composition which masks the taste of particularly bitter of unpleasant tasting drugs. It is an object of the present invention to address this need.
According to the present invention there is provided a taste-masked composition comprising a drug, an ion-exchange resin and a polymeric coating material wherein the drug is bound to the ion-exchange resin to form a drug-resin complex, and the polymeric coating material is applied to said drug-resin complex to form a coating layer covering the drug-resin complex.
The term “bound” as used herein includes also a drug adsorbed to the ion-exchange resin.
Also provided are dosage forms for oral administration comprising a taste masked
· composition according to the invention.
The combination of complexing the drug with an ion-exchange resin and coating the resultant drug-resin complex in accordance with the invention provides good taste masking and facilitates the incorporation of the drug into dosage forms for oral administration. Complexing the drug with an ion-exchange resin prevents leaching of drug from the formulation and thus the likelihood of a bitter taste in the case of a formulation such as a fast melt tablet or liquid formulation.
Any drug compound which is characterised by an unpleasant taste or odour and which can be bound to an ion-exchange resin may be used in the present invention. Representative drugs include, but are not limited to, H2 receptor antagonists, antibiotics, analgesics, cardiovascular agents, peptides or proteins, hormones, anti-migraine agents, anti-coagulant agents, anti-emetic agents, anti-hypertensive agents, narcotic antagonists, chelating agents, anti-anginal agents, chemotherapy agents, sedatives, anti-neoplastics, prostaglandins, antidiuretic agents and the like. Typical drugs include, but are not limited to, nizatidine, cimetidine, ranitidine, famotidine, roxatidine, etinidine, lupitidine, nifentidine, niperitone, sulphotidine, tuvatidine, zaltidine, erythromycin, erythromycin derivatives such as for example ketolide (1 l,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl3-O-methyl-alpha-L-ribohexopyranosyl)oxy)-6-O-methyl-3-oxo-12,1 l-(oxycarbonyl(4(4-(3-pyridinyl)-lH-imidazol-l-yl)butyl)imino)) erythromycin), penicillin, ampicillin, roxithromycin, clarithromycin, psylium, ciprofloxacin, theophylline, nifedipine,prednisone, prednisolone, ketoprofen, acetominophen, ibuprofen, dexibufen lysinate, flurbiprofen, naproxen, codeine, morphine, sodium diclofenac, acetyl salicylic acid, caffeine, pseudoephedrine, phenylpropanolamine, diphenyhydramine, chlorpheniramine, dextrometorphan, berberine, loperamide, mefenamic acid, flufenamic acid, astemizole, terfenadine, certrizine, phenytoin, guiafenesin, N-acetylprocainamide hydrochloride, pharmaceutically acceptable salts thereof and derivatives thereof.
Ion-exchange resin materials suitable for use in accordance with the present invention include any ion-exchange resin which is capable of binding the drug, including for instance anionic and cationic resin materials. Where the drug is a cation or is prone to protonation, the ion-exchange resin is suitably a cation exchange resin material. That is to say, a resin having a predominantly negative charge along the resin backbone, or a resin having a pendant group suitable for cation exchange, and which has an affinity for positively charged ions or cationic species. Typical of such cation exchange resins include resins having polymer backbones comprising styrene - divinyl benzene colpolymers, methacrylic acid and divinyl benzene co-polymers, and resins with pendant functional groups suitable for cation exchange, such as sulphonate and carboxylate groups. Cation exchange resins suitable for use in the practice of the present invention include for example those sold under the trade names Amberlite IRP64, Amberlite ERP-69 and Amberlite IRP 88 (Rohm and Haas, Frankfurt, Germany),
Dowex 50WX2-400, Dowex 50WX4-400 and Dowex 50WX8-400 (The Dow Chemical Company, Midland, MI), Purolite C115HMR and Purolite C102DR (Purolite International Ltd., Hounslow, Great Britain).
Similarly, where the drug is an anion or is prone to deprotonation, the ion exchange resin is suitably an anion exchange resin material. That is to say, a resin having a predominantly positive charge along the resin backbone, or a resin having a pendant group suitable for anion exchange, and which has an affinity for negatively charged ions or anionic species. Typical of such anion exchange resins include resins having polymer backbones comprising styrene, acrylic acid or phenol units, co-polymers thereof, styrene-divinyl benzene co-polymers and phenolic-based polyamine condensates and resins with pendant functional groups suitable for anion exchange, such as ammonium or tetraalkyl ammonium functional groups. Anion exchange resins suitable for use in the practice of the present invention include for example those sold under the trade names Amberlite IRP-58, Amberlite IRA-67, Amberlite IRA 68 (Rohm and Haas, Frankfurt, Germany), Dowex 1X2-400, Dowex 1X4-400, Dowex 1X8-400 and Dowex 2X8-400 (The Dow Chemical Company, Midland, MI), Purolite A845, Purolite A500P and Purolite PCA-433 (Purolite International Ltd., Hounslow, Great Britain), Duolite API43/1092 and Duolite A143/1093.
Resins with various degrees of crosslinking and a range of binding capacities may also be used in the practice of the present invention.
Typically the ion-exchange resins suitable for use in the present invention are in the form of ion-exchange resin particles. Stirring the ion-exchange resin particles in a solution of the selected drug is usually sufficient to achieve binding of the drug onto the resin particles. Loading of the resin is suitably carried out at a pH which facilitates binding of the drug compound. Some ion-exchange resins may require “activation” by rinsing with a solution of acid or base, prior to loading with the drug. Such activation requirements will be well known to. those skilled in the art of working with ionexchange resin materials. Specific requirements for individual ion-exchange resin materials may be obtained from the resin manufactures.
The polymer material used in coating the drug-resin complex may comprise a pH independent or pH dependent coating material. pH independent coating materials suitable for use in the present invention include, for example, alkyl celluloses such as methyl cellulose, hydroxyalkyl alkyl celluloses such as hydroxy propyl methyl cellulose, hydroxy alkyl celluloses such as hydroxy propyl cellulose and hydroxy ethyl cellulose, polyvinyl alcohol, maltodextrin, polymethacrylates such as Eudragit® RL (Rohm5 Pharma, Darmstadt, Germany). A particularly useful pH independent polymer for us e in accordance with the present invention is Eudragit ®RD 100 (Rohm-Pharma, Darmstadt, Germany). A particularly useful pH dependent coating material suitable for use in accordance with the present invention is Eudragit® E (Rohm-Pharma, Darmstadt, Germany). The polymeric coating may suitably comprise a combination of two or more polymer materials.
The coating may be applied to the drug loaded particles by any suitable technique. Such techniques will be apparent to those skilled in the art. Particularly useful for application of the coating is the technique of spray coating, carried out for instance using a fluidised bed coating apparatus. Suitable excipients and / or additives may be added to the coating formulations. For example it may be desirable to add plasticisers, glidants, antitacking agents, pigments and other excipients to the coating formulations. Suitable plasticisers include, for example, triethyl citrate and polyethylene glycol. Suitable glidants include, for example, talc, syloid, glycerol monostearate and magnesium stearate. The coating material may be applied to the drug loaded particles in any amount which is sufficient to give the desired taste-masking characteristics. Typically the coating material is applied in an amount equivalent to 10 - 300 % by weight of the drugloaded resin particles. Preferably, the coating material is applied in an amount equivalent to 20 - 250 % by weight of the drug loaded resin particles.
Taste-masked coated drug loaded resin compositions according to the present invention may be adapted for a range of final oral dosage forms, including controlled release dosage forms. Suitable final dosage forms include, for example, suspension, syrup, capsule, tablet, sprinkle, sachet, effervescent tablet, fast melt tablet, fast dissolving tablet and disintegrating tablet forms. For example, the drug loaded, coated ionexchange resin particles may be formulated in a suspension and freeze-dried to form a fast dissolving or disintegrating tablet. The taste-masked compositions according to the invention may also be formulated in solid form which is reconstituted as a suspension prior to administration without losing any taste masking property.
Drug loaded, coated resin particles of any size suitable for incorporation into any one of 5 the abovementioned final dosage forms may be used in the practice of the invention.
The invention will be further illustrated by the following Examples.
Example 1
Ketolide (11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo hexopyranosyI)oxy)-6-O-methyl-3-oxo-12,11 -(oxycarbonyI(4-(4-(3-pyridinyl)-IHimidazol-l-yl)butyl)imino)) erythromycin), also referred to below as “the active ingredient” or “ketolide” composition.
In the case of the abovementioned ketolide a taste-masked powder formulation would be attractive due to the unpleasant taste characteristics of the drug. The physicochemical properties of this compound are such that as the pH of the drug in solution is lowered the drug is completely ionised, each of three nitrogen atoms being protonated according · to their respective pKa values. The protonated drug may then be loaded onto a cationic exchange resin (such as a cation exchange resin material as listed above) to form a drugresin complex. However, binding of this active ingredient to the ion-exchange resin is not sufficient to completely mask the taste of the drug as judged by a panel of seven. In this case coating the drug-resin complex with a coating polymer results in a composition possessing the required taste masked and organoleptic character. The formulation of a taste masked ketolide composition according to the invention is given below.
Two placebo granulates were prepared, the first having a flavouring agent added intragranularly and the other having the flavouring agent added extra-granuiarly. Details of the placebo granulates are given in Table 1. The granulates were prepared as follows: the raw materials were dry mixed; purified water was added slowly until effective granulation was achieved and the granulate was left to tray-dry in an oven at ca 40 °C overnight. This resulting granulate was size-reduced through a 0.25 mm screen using an
Erweka oscillating granulator to form a fine granulate. In the case of the intra-granuJar mix, the peppermint oil was added prior to the addition of water. In the case of the extra-granular mix, the peppermint oil was added to the fine granulate.
Material “Intra-granular” (g) “Extra-granular” (g) Xylisorb 300 86.74 86.98 Neosorb P60 86.74 86.98 Critic acid 5.00 5.00 Aspartame 1.04 1.04 Kollidon 30 20.00 20.00 Peppermint oil 0.48 4.67
Table 1, Composition of placebo granulate with peppermint flavour added intragranularly and extra-granularly.
The cation exchange resin (Dowex 50WX2-400, 2 Kg) was washed with purified water (5 L) for 15 min. The washed resin was recovered and loaded with the active ingredient • to a potency of 400 mg drug / g drug loaded resin by mixing the resin in a solution of 8 % active ingredient in 1 N HC1 for 60 min. The loaded resin was recovered by filtration, washed with purified water and oven dried at 40 °C.
The drug-resin complex was then mixed with the placebo granulate described above to form an uncoated drug-resin ketolide composition. Three different ratios of drug-resin complex to granulate were prepared using (i) the “intra-granular” and (ii) “extra20 granular” placebo respectively in the following ratios: 75 : 25 (drug-resin complex :
' granulate); 50 : 50 (drug-resin complex : granulate); and 25 : 75 (drug-resin complex :
granulate).
The uncoated drug-resin ketolide compositions thus prepared were found to have improved taste characteristics compared to the raw drug, but still had an unpleasant after taste. The taste of the resin material itself may have contributed to this.
Example 2
Taste-masked ketolide (1 l,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl)oxy)-6-0-methyl-3-oxo-12,11 -(oxycarbonyl(4-(4-(3pyridinyl)-lH-imidazol-l-yl)butyl)imino)) erythromycin), also referred to below as “the active ingredient” or “ketolide” composition.
The cation exchange resin (Dowex 50WX2-400, 2 Kg) was washed with purified water (5 L) for 15 min. The washed resin was recovered and loaded with the active ingredient to a potency of 400 mg drug / g drug loaded resin by mixing the resin in a solution of 8 % the active ingredient in 1 N HC1 for 60 min. The loaded resin was recovered by filtration, washed with purified water and dried in a Uniglatt (Glatt Air Techniques, ) at 40 °C.
The uncoated drug-resin ketolide compositions prepared above was then coated in a
Glatt GPCGl, with a 15 % aqueous solution of Eudragit RD 100 : Syloid 244 FP : Polysorbate 80 (5:1:1) to a level of 50 % weight gain with Eudragit RD 100, at a spray rate of 8 g / min and product temperature of 23-27 °C. The particle size of the 50 % coated resin was determined by a dry powder method in a Malvern Mastersizer S (Malvern Instruments Limited, Malvern, Worcestershire, UK) as the following: Dv.io =
95.37μιη, Dv50 = 125.53 pm, DVi90 = 167.85 pm. The coated drug-resin complex was found to be essentially tasteless.
Claims (12)
1. A taste-masked composition comprising a drug, an ion-exchange resin and a polymeric coating material wherein the drug is bound to the ion-exchange resin to 5 form a drug-resin complex, and the polymeric coating material is applied to said drug-resin complex to form a coating layer covering the drug-resin complex.
2. A taste-masked composition according to claim 1, wherein the drug has a strong and unpleasant taste or odour.
3. A taste-masked composition according to claim 1 or 2, wherein the ion exchange resin is an anion exchange resin.
4. A taste-masked composition according to claim 1 or 2, wherein the ion exchange 15 resin is a cation exchange resin.
5. A taste-masked composition according to any one of claims 1 to 4, wherein the polymeric coating material is a pH independent polymer. 20'
6. A taste masked composition according to any one of claims 1 to 4, wherein the polymeric coating material is a pH independent polymer.
7. A taste-masked composition according to any one of claims 1 to 6, wherein the polymeric coating material comprises a combination of two or more polymer 25 materials.
8. An oral dosage form comprising a taste-masked composition according to any one of claims 1 to 7. 30
9. An oral dosage form according to claim 8, which is a solid oral dosage form selected from capsule, tablet, sprinkle, sachet, effervescent tablet, fast melt tablet, fast dissolving tablet and disintegrating tablet forms.
10. A solid oral dosage form comprising a taste-masked composition according to any one of claims 1 to 7, which may be reconstituted as a suspension prior to administration.
11. A taste-masked composition acording to claim 1, substantially as hereinbefore described and exemplified.
12. An oral dosage form according to claim 8, substantially as hereinbefore described 10 and exemplified.
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE990009A IE990009A1 (en) | 1999-01-07 | 1999-01-07 | Taste-masked composition |
JP2000591981A JP2002534374A (en) | 1999-01-07 | 2000-01-07 | Multiparticulate oral dosage form |
PCT/IE2000/000003 WO2000040224A1 (en) | 1999-01-07 | 2000-01-07 | Multiparticulate oral dosage forms |
AU19982/00A AU1998200A (en) | 1999-01-07 | 2000-01-07 | Multiparticulate oral dosage forms |
EP00900315A EP1140037A1 (en) | 1999-01-07 | 2000-01-07 | Multiparticulate oral dosage forms |
CA002355829A CA2355829A1 (en) | 1999-01-07 | 2000-01-07 | Multiparticulate oral dosage forms |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE990009A IE990009A1 (en) | 1999-01-07 | 1999-01-07 | Taste-masked composition |
Publications (1)
Publication Number | Publication Date |
---|---|
IE990009A1 true IE990009A1 (en) | 2000-07-12 |
Family
ID=27620459
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE990009A IE990009A1 (en) | 1999-01-07 | 1999-01-07 | Taste-masked composition |
Country Status (1)
Country | Link |
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IE (1) | IE990009A1 (en) |
-
1999
- 1999-01-07 IE IE990009A patent/IE990009A1/en unknown
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