Patent Application
20060127479
The present invention provides a taste masked pharmaceutical composition comprising (a) a core comprising a bitter tasting drug, such as cetirizine dihydrochloride; and (b) a coating comprising a cationic co-polymer based on mono- or dialkylaminoalkyl methacrylate and neutral acrylic or methacrylic esters, wherein said composition is prepared by a process which is essentially free of an organic solvent.
Cetirizine (C21H25ClN2O3) is also known as [2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid or [2-[4-[(p-chloro-α-phenylbenzyl)-1-piperazinyl]ethoxy]acetic acid. Cetirizine is a human metabolite of hydroxyzine. Cetirizine is useful as an antiallergen, spasmolytic, and a histamine H2-antagonist and is generally non-sedating. See U.S. Pat. No. 4,525,358 (the '358 patent) and The Merck Index, Eleventh Edition, Page 310, Entry 2013 (1989). Cetirizine belongs to a class of drugs known as substituted benzhydrylpiperazines which characteristically have an extremely bitter taste.
Various techniques intended to mask the taste of such drugs have been described. Simple approaches include adding flavoring or sweetening ingredients to the compositions. When simple approaches are ineffective, various other approaches are used. An example of one such approach is to create a physical barrier to the drug from the saliva. Cationic co-polymers synthesized from dimethylaminoethylmethacrylate and neutral methacrylic acid have been employed as a barrier material. However, such barrier co-polymers generally require that an organic solvent be used during formulating. For example, U.S. Pat. No. 5,286,489 teaches ethyl alcohol as a solvent for a methyl methacrylic ester co-polymer. U.S. Pat. No. 4,708,867 teaches acetone and isopropyl alcohol as solvents for a first coating of polyvinylpyrrolidone, and a second coating of a dimethylaminoethyl and methyl methacrylate co-polymer. U.S. Pat. No. 4,760,093 teaches methylene chloride as a solvent for a dimethylaminoethyl and methyl methacrylate and neutral methacrylic acid esters.
U.S. Pat. No. 3,558,600 describes a method for masking the bitter taste of antihistaminic agents belonging to the substituted 1-(p-chloro-benzhydryl)piperazine family, which involves converting the active substance in free base form into the form of its salt with a long-chain alkyl sulphate, such as stearyl sulphate.
U.S. Pat. No. 4,525,358 describes cetirizine and methods for achieving an antiallergic, antihistaminic, bronchodilator and antispasmodic effect in a patient by administering cetirizine. This patent describes only one formulation which contains 100 mg of cetirizine, 67 mg of lactose, 1 mg of magnesium stearate and 2 mg of silicon dioxide.
U.S. Pat. No. 6,455,533 (the '533 patent) describes pharmaceutical compositions for oral administration containing an active substance belonging to the substituted benzhydrylpiperazine family and cyclodextrin. According to this patent there are two methods for masking the taste of the active substances in a solid pharmaceutical composition for oral administration. In the first method, an inclusion complex is formed between the active substance and a cyclodextrin. In the second method, an inclusion complex is not formed between the active substance and cyclodextrin. However in both methods, cyclodextrin must be present. The FDA's Orange Book lists the '533 patent as a formulation covering ZYRTEC® Chewable Tablets, which are commercially-available from Pfizer. The tablets contain 5 mg or 10 mg of cetirizine hydrochloride, acesulfame potassium, artificial grape flavour, betadex, NF (β-cyclodextrin), blue dye, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, natural flavour and red dye (carmine).
U.S. Pat. No. 5,489,436 (the '436 patent) describes chewable tablets prepared from a coated medicament wherein the coating is a “reverse enteric coating” designed to be soluble at the acidic pH of the stomach but relatively insoluble in the mouth. The coatings comprise a polymer mixture of dimethylaminoethyl methacrylate and neutral methacrylic acid ester and a cellulose ester. The '436 patent does not teach substituted benzhydrylpiperazine compounds, and additionally requires a cellulose ester, such as cellulose acetate or cellulose triacetate, in the coating. In addition, the '436 patent teaches methanol and acetone as solvents for a polymer mixture of dimethylaminoethyl methacrylate and neutral methacrylic acid ester.
The prior art discussed above either requires the use of an organic solvent during the preparation of taste masked pharmaceutical compositions containing a cationic co-polymer of dimethylaminoethylmethacrylate and neutral methacrylic acid, or requires a cyclodextrin. However, organic solvents present handling issues in the workplace and are environmentally hazardous. Even residual organic solvents may deleteriously effect human health. Thus, it would be desirable to prepare a taste masked pharmaceutical composition for oral administration containing a cationic co-polymer of dimethylaminoethylmethacrylate and neutral methacrylic acid without the use of organic solvents.
The invention provides a taste masked pharmaceutical composition comprising:
According to another aspect, the invention provides a process for preparing a taste masked pharmaceutical composition, said process comprising:
According to another aspect, the invention provides a process for preparing a taste masked pharmaceutical composition, said process comprising: applying a coating on a bitter tasting drug, wherein the coating comprises an aqueous dispersion of a pharmaceutically acceptable cationic co-polymer based on mono- or di-alkylaminoalkyl methacrylate and neutral acrylic or methacrylic esters, wherein the alkyl group independently has 1 to 6 carbon atoms, to form a composition.
According to another aspect, the invention provides a process for preparing a taste masked pharmaceutical composition, said process comprising:
The present inventors have unexpectedly determined that the taste masked pharmaceutical compositions of the invention may be prepared without using an organic solvent or a cyclodextrin.
The invention provides a taste masked pharmaceutical composition comprising:
It is within the scope of the invention to coat the bitter tasting drug without first mixing the bitter tasting drug with a binder, inert carrier, or other excipients. For example, crystals of the bitter tasting drug may be coated with a pharmaceutically acceptable cationic co-polymer based on mono- or dialkylaminoalkyl methacrylate and neutral acrylic or methacrylic esters, wherein the alkyl group independently has 1 to 6 carbon atoms.
The bitter tasting drug is not limited with the proviso that it is used as a medically active component and has a bitter taste. Examples of such drugs include: central nervous system drugs such as a hypnotic sedative, a sleep inductor, an anxiolytic drug, an antiepileptic, an antipyretic-analgesic-anti-inflammatory drug, an antidepressant, a histamine H2-antagonist, a 5-HT agonist, an antiparkinsonism drug and a psychoneurosis drug, circulatory drugs such as a skeletal muscle relaxant, an autonomic drug, an antispasmodic agent, a cardiotonic agent, an arrhythmia drug, a diuretic agent, an antihypertensive drug, a vasoconstrictor, a coronary vasodilator, a peripheral vasodilator and a hyperlipemia drug, allergy drugs such as an antitussive expectorant and a bronchodilator, digestive organ drugs such as an antidiarrheal drug, a drug for controlling intestinal function, an antiulcer drug, a stomatic digestive drug and an antacid agent and hormone drugs such as a pituitary hormone drug, a thyroid hormone drug and an anti-thyroid hormone drug, as well as a urogenital organ drug, a vitamin compound, a hemostatic drug, a blood coagulation inhibitor, a pulmonary disease drug, an antidote, a habitual intoxication drug, a gout treating drug, a diabetic drug, an anti-malignant tumor drug, an antibiotic, a chemotherapy drug, an anthelmintic drug and an anti-protozoan drug. The bitter tasting drug is preferably selected from a histamine H2-antagonist, a 5-HT agonist, an antibiotic, or a nonsteriodal anti-inflammatory drug. More preferably, the bitter tasting drug is a histamine H2-antagonist. A mixture of bitter tasting drugs may also be used.
Preferred bitter tasting drugs include, but are not limited to, loperamide, sildenafil, topiramate, citalopram, mirtazapine, desloratadine, enalapril, lorazepam, zopiclone, selegline, lorazepam, risperidone, ondansetron, olanzapine, almotriptan, frovatriptan, naratriptan, sumatriptan, zolmitriptan, rizatriptan, cimetidine, ranitidine, famotidine, nizatidine, etinidine, lupitidine, nifentidine, niperotidine, roxatidine, sulfotidine, tuvatidine, zaltidine, penicillin, ampicillin, erythromycin, acetaminophen, caffeine, dextromethorphan, diphenhydramine, theophylline, spironolactone, chloropheniramine, nabumetone, ibuprofen, naprosyn, ketoprofen, astemizole, azatadine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyproheptadine, dexchlorpheniramine, dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, loratadine, phenindamine, terfenadine, tripelennamine, effective salts thereof and derivatives thereof.
As used herein, “cetirizine” refers to [2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid or [2-[4-[(p-chloro-α-phenylbenzyl)-1-piperazinyl]ethoxy]acetic acid and pharmaceutically acceptable salts thereof. Preferred salts are acid addition salts, especially the dihydrochloride, referred to also herein as the “hydrochloride”. Most preferably, the bitter tasting drug is cetirizine dihydrochloride.
The bitter tasting drug is present in the pharmaceutical compositions in an amount of from about 0.1 weight percent (wt. %) to about 20 wt. %, based on the total weight of the pharmaceutical composition. Preferably, the bitter tasting drug is present in an amount of from about 1 wt. % to about 5 wt. %, more preferably about 2 wt. %, based on the total weight of the composition.
Examples of binders include, but are not limited to, methylcellulose, carboxymethycellulose sodium, ethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, gelatine, polyvinyl alcohol, acacia, tragacanth, guar, pectin, starch paste, pre-gelatinized starch, sucrose, corn syrup and sodium alginate. A preferred binder is polyvinylpyrrolidone. A mixture of binders may also be used.
The binder is present in the pharmaceutical compositions in an amount of from about 0.1 wt. % to about 20 wt. %, based on the total weight of the pharmaceutical composition. Preferably, the binder is present in an amount of from about 1 wt. % to about 5 wt. %, more preferably about 2 wt. %, based on the total weight of the composition.
The inert carrier may be water soluble or water insoluble. Examples of inert carriers include, but are not limited to, spray-dried or anhydrous lactose, sucrose, dextrose, starch, pre-gelatinized starch, mannitol, maltitol, sorbitol, xylitol, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate and calcium sulphate. A preferred inert carrier is microcrystalline cellulose. A mixture of inert carriers may also be used.
The inert carrier is present in the pharmaceutical compositions in an amount of from about 15 wt. % to about 80 wt. %, based on the total weight of the pharmaceutical composition. Preferably, the inert carrier is present in an amount of from about 40 wt. % to about 65 wt. %, more preferably about 54 wt. %, based on the total weight of the composition.
The coating component of the compositions of the invention contains a pharmaceutically acceptable cationic co-polymer based on mono- or di-alkylaminoalkyl methacrylate and neutral acrylic or methacrylic esters, wherein the alkyl group independently has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Preferably, the cationic co-polymer is based on dimethylaminoethyl methacrylate and neutral methacrylic acid esters (EUDRAGIT® E 100). EUDRAGIT® E 100 is available from Degussa Rohm Pharma Polymers. EUDRAGIT® EPO is a powdered form of EUDRAGIT® E 100. In addition, EUDRAGIT® E 100 is also known as aminoalkylalkyl methacrylate copolymer E and basic butylated methacrylate copolymer E.
The cationic co-polymer based on mono- or di-alkylaminoalkyl methacrylate and neutral acrylic or methacrylic esters is preferably soluble in acidic environments where the pH is up to about 5. At a pH greater than about 5, the co-polymer is preferably insoluble in water. Thus, the co-polymer is preferably insoluble in the mouth of a patient where the pH is about 7.
The cationic co-polymer is present in an amount of from about 0.5 wt. % to about 15 wt. %, based on the total weight of the pharmaceutical composition. Preferably, the cationic co-polymer is present in an amount of from about 1 wt. % to about 5 wt. %, more preferably about 3 wt. %, based on the total weight of the composition.
According to the process of the invention, the coating is applied to the granules in an amount which provides a taste masking effect for a relatively short period during which the composition, for example, is chewed by the patient, and which allows the dosage form to be broken into smaller particles allowing it to be easily swallowed, making it more palatable which results in better patient compliance.
The pharmaceutical compositions of the invention may contain one or more excipients in addition to the binder and inert carrier previously mentioned to enhance the palatability of the dosage form and to improve the taste. Examples of excipients include, but are not limited to, diluents, fillers/bulking agents, effervesant salts, disintegrants, lubricants, glidants, emulsifiers, electrolytes, wetting agents, solubilizers, surfactants, colors, flavors, pigments, anti-caking agents, sweeteners, and effervescent couples. A mixture of excipients may also be used. Such excipients are known to those skilled in the art, and thus, only a limited number will be specifically referenced. Preferably, the excipients meet the standards of the National Formulary (NF) or United States Pharmacopoeia (USP).
Examples of disintegrants include:
Examples of glidants include, but are not limited to, silica, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate. A preferred glidant is talc.
Examples of lubricants include, but are not limited to, vegetable oils, such as hydrogenated vegetable oil or hydrogenated castor oil; polyethylene glycols, such as polyethylene glycol (PEG)-4000 and PEG-6000; stearic acid; salts of stearic acid, such as magnesium stearate, sodium stearate and sodium stearyl fumarate; mineral salts, such as talc; inorganic salts; organic salts, such as sodium benzoate, sodium acetate and sodium oleate; and polyvinyl alcohols.
Examples of preferred surfactants include:
More preferably, the surfactant is selected from polyoxyethylene(20)sorbitanmonooleate, glycerol monostearate, glycerol monolaurate, glycerol monopalmitate, glycerol monooleate, glycerol monocaprylate, sodium lauryl sulphate, cetyltrimethyl ammoniumbromide, and dioctylsodium sulfosuccinate. A mixture of surfactants may also be used.
In one embodiment of the invention, the pharmaceutical composition is in the form of a solid dosage form which contains coated granules comprising a bitter tasting drug, a binder, an inert carrier, a cationic co-polymer based on mono- or di-alkylaminoalkyl methacrylate and neutral acrylic or methacrylic esters, and a mixture of excipients. A preferred ratio of the mixture of excipients, including the amount of binder and diluent, to the coated granules is from about 0.4:1 to about 5:1. More preferably, the ratio is from about 0.4:1 to about 2:1. Most preferably, the ratio is about 0.6:1.
One of the advantages of the pharmaceutical compositions of the invention is that they provide a method for formulating extremely palatable solid dosage forms which contain bitter tasting drugs. Solid dosage forms include sprinkles, capsules, caplets, powders and tablets. In one embodiment, the compositions are compressed into a tablet. Tablets may include multiple layer compressed tablets, bi-layer tablets, effervescent tablets, mouth dissolving tablets, water dispersible tablets, and chewable tablets. Preferably, the tablets are chewable, orally disintegrating or dissolving. The tablet formulation can be prepared by wet granulation, dry granulation, direct compression or by any other technique known in the pharmaceutical art.
In a preferred embodiment of the invention, the pharmaceutical composition is in the form of a chewable tablet which comprises:
In one embodiment of the invention, the taste masked pharmaceutical compositions are prepared by a process comprising:
In one embodiment of the invention, the taste masked pharmaceutical compositions are prepared by a process comprising: applying a coating on a bitter tasting drug, wherein the coating comprises an aqueous dispersion of a pharmaceutically acceptable cationic co-polymer based on mono- or di-alkylaminoalkyl methacrylate and neutral acrylic or methacrylic esters, wherein the alkyl group independently has 1 to 6 carbon atoms, to form a pharmaceutical composition.
In one embodiment of the invention, the taste masked pharmaceutical compositions are prepared by a process comprising:
According to the processes of the invention, the loading of the bitter drug as a solution or dispersion over the core granules or agglomerates may be carried out by one or more granulation, spray coating, or coacervation techniques. The core granules or agglomerates prepared in the processes according to the invention, preferably have a particle size from about 180 to 420 microns.
The following non-limiting examples illustrate further aspects of the invention.
Preparation of a Chewable Tablet Composition Containing 5 mg of Cetirizine Dihydrochloride.
*EUDRAGIT ® EPO is the powder form of EUDRAGIT ® E100.
The tablets are prepared according to the following procedure:
Preparation of a Chewable Tablet Composition Containing 5 mg of Cetirizine Dihydrochloride.
*EUDRAGIT ® EPO is the powder form of EUDRAGIT ® E100.
The tablets are prepared according to the following procedure:
While the invention has been described with particular reference to certain embodiments thereof, it will be understood that changes and modifications may be made by those of ordinary skill within the scope and spirit of the following claims:
