WATERLESS THIXOTROPIC COMPOSITION

Abstract: A waterless thixotropic composition of a medicament, particularly for oral administration, comprises from 0.5 to 10% by weight of a drug having a therapeutic or prophylactic effect on a condition affecting an animal, from 2 to 25% by weight of a hydroxylated fatty acid ester of glycerin, from 55 to 97.2% by weight of a glycol or glycerin; and from 0.3 to 15% by weight of a water-soluble polymer. Waterless compositions are particularly necessary where water content would result in decomposition of the medicament formulation.

Description: WATERLESS THIXOTROPIC COMPOSTTION This invention relates to medicament formulations and compositions that are administered to animals. More particularly it relates to thixotropic compositions of medicament that are administered by means of a incremental delivery device such as that disclosed in U.S.S.N. 261,326, filed May 7, 1981. Even more particularlv this invention relates to stable semi-solid formulations of macrolide antibiotics such as C-076 which is described in U.S. 4,199,579. In the delivery of medicaments to animals it has been found particularly difficult to administer doses in the form of tablets or bolus. The animals tend to reject the close unless it is thrust so deeply into their throats that they cannot block ingestion with their tongues or otherwise. In practice this is difficult for one other than a trained animal handler to accomplish. Other available means of administration include dosing the drinking water or the feed. In administration through drinking water-- stability problems of the drug are sometimes encountered, and with both administration through feed and water unacceptable variations of dosaae can result hecause individual animal's food and water requirements are not uniform. One desirable means for administering medicament to an animal is to squeeze an incremental dose of semi-solid medicament in the form of a paste or gel into the animals mouth, most suitably onto the tongue. A paste which is sufficiently sticky that the animal cannot expel it is ultimately ingested. A desirable characteristic of a satisfactory paste composition is that it be thixotropic; that is, the composition is fluid only when pressure or shear is applied during the dosing procedure. This allows for easy fluid-like administration without hiving the paste leak from the undisturbed delivery cartridge. Another desirable characteristic is that formulation should be sufficiently sticky so that there is no loss of the formulation once administered. The paste, of course. must also be palatable to the animal to to ensure that it is totally consumed after administration. Otherwise, even though the paste tends to adhere to the tongue1 if the taste is severely objectionable. the animal attempts to work the dose from the mouth, sometimes with partial success. A paste is free of entrained air so as to eliminate sponginess which leads to two problems if it is present. First there can be incorrect dose delivery wince the compression of the formulation takes place the instant pressure is applied. Also slow expansion back at the normal volume can result in after-dose oozing from. the formulation delivery device. Another desirable characteristic is that the paste shouid incorporate a fairly high concentration of drug so as to maximize the number of dosages deliverable from a cartridge. While many dosage formulations for many orugs are available, most of them contain a sufficient amount of water for use as a solvent or as an ingredient which is required for gel formation. These formulations are impractical for use with any formulation wherein the medicament or other component is sensitive to chemical attack by the water. Such attack would include hydrolysis or any other means whereby decomposition occurs and alters the therapeutic index of the drug. The delivery techniques of pastes are well known and need not be dealt with here in detail. In general, in horses the paste is deposited on the posterior portion of the tongue through the interdental space on either side of the head. In cattle the dose can be thrust directly on the tongue. The paste formulation of this invention is a rour-component system comprising first a triester of glycerin and a hydroxylated fatty acid where the fatty acid residue is from 10 to 22 carbon atoms in length and has at least one hydroxy substituent. The preferred ester is trihydroxostearin which is a trieste of glycerin and hydroxystearic acid. The second component or the system is an alkylene dihydric alcohol such as an alkylene glycol of from 3 to 6 caroon atoms; alkylene pinacol of from 4 to 6 carbon atoms, glycerol, or a lower molecular weight plyalylene glycol in the molecular weight range of about 200 to about 2000. The preferred glcols are propylene glycol and polyethylene glycol. The term alkylene as used herein means an alkylene having less than six carbon atoms. The third component is a water soluble polymer, most suitably a cellulose serivative. The fourth component is the medicament. Generally, the molecular weight of the water soluble polymer is not material to the inventionhowever, low molecular weights appear to be desirable since they impart less stringyness to the paste formulation. To this end, molecular weights of 60,000 or less to about 100,000 or more are preferred although molecular weights can range from 50,000 to 1,000,000 or more. Generally all polymers that are soluble in water as well as in organic solvents such as lower alcohols and are considered as generally recognized as safe are appropriate for use in this composition. Such polymers include lower alkyl (C1 to C4) ether and ester cellulose derivatives, such as hydroxypropyl cellulose, and hydroxypropylmethyl cellulose; carboxyvinyl polymers available under the tradename carbopol from B. F. Goodrich polvvinyl pyrrolidone; and poly (methylvinylether maleic anhydride) available under the trade name GANTREZ. The preferred polymer is hydroxypropyl cellulose. Generally, the hydroxylated fatty acid component is present in from 2 to 25% by weight; the glycol from 55 to 97.2% by weight; and the water soluole polymer fron 0.3 to 15% hy weight. she above carrier composition incorporates from 0.5% to 10% by weight of a medicament for therapeutically or prophylactically treating animals. There can also be employed colorants, flavors, or opaquing agents such as titanium dioxide. As the medicament portion of the composition increases, it is more desirable to reduce the glycol content rather than the fat or polymer components. Thus, in a heavily drug loaded paste, there would be: hydroxypropyl cellulose 5.0% by t. trihydroxystearin 12.0% by wt. medicament 10.0% by wt. propylene glycol 73.0% by wt. In the more suitable compositions there are employed 10 to 15% by weight hydroxylated fatty acid, 3 to 8% by weight water soluble polymer, 0.1 to 5% by weight of medicament and the remainder being glycol. In a preferred composition there is: C-076 0.5% bv wt. hydroxypropyl cellulose (Klucel EF) 5.0% by wt. trihydroxystearin 12 0t by wt. propylene glycol 825% by wt In this preferred composition there also can be added sufficient titanium dioxide to render to composition opaque and thereby result not only in a more elegant paste, but one that transmits ultra-violet light to a lesser degree and protects the medicament from UV irradiation. To the total weight of the composition is added from 0.2 to 5% titanium dioxide. To prepare the formulation, the drug and polymer are dissolved, but at least until the admixture admixed with the glycol preferably until it is homogeneous. To achieve dissolution or homogeniety, it is preferable that the drug and polymer be of a small particle size or powdered, If dissolution upon trial is found to be incomplete, then to obtain as complete a dispersal as practical, the polymer or drug are suitably micronized prior to admixing with glycol. Drugs or polymers that are liquids of course pose fewer admixing problems. After dispersal of the drug and polymer in the qlycol is complete, the hydroxylate fatty acid ester is added. While aaitating vigorously suitably with the aid of a high speed impeller, the hydroxylated fatty acid is added in increments such that complete dispersal of the newly added increment is obtained before adding additional hydroxylated fatty acid. This addition of the hydroxylated fatty acid is desirably accompanied by heating the admixture to 40-65"C, or preferably to 55-600C. If round that heating is not required to achieve dissolutionr it is nevertheless generally preferable to heat the admixture of polymer, glycol hydroxylated fatty acid, and drug to about 50-65 C, and most preferably to 55-60-C to improve the viscosity of the formulation and achieve optimum dispersal. It is at this stage that any flavoring agents colorants, or opaquing agents can be added and dispersed throughout the formulation. After cooling, the formulation is packaged in suitable containers.

Claims: EMI7.1 1. An essentially anhydrous gel formulation for administration to animals comprising from 0.5 to 10% by weight of a drug having a therapeutic or prophylactic effect on a condition affecting an animal, from 2 to 25% by weight of a hydroxylated fatty acia ester of glycerin, from 55 to 97.2% by weight of a glycol or glycerin; and from 0.3 to 15% by weight of a water soluble polymer. 2. A formulation according to Claim 1 where the glycol is polyethylene glycol. 3. A formulation according to Claim 1 where the giycol is propylene glycol. 4. A formulation according to Claim 1 where the hydroxylated fatty acid of the ester has from 10 to 22 carbon atoms. 5. A formulation 'where the hydroxylated fatty acia ester has from 10 to 18 carbon atoms and at least one hydroxy substituent. 6. A formulation according to Claim 5 where the hydroxylated fatty acid is trihydroxystearin. 7. A formulation according to Claim 1 where the drug is the macrolide C-076. 8. A formulation according to Claim 1 where the polymer is a lower alkyl ether or ester of cellulose. 9. A formulation according to Claim. 1 where the polymer has less than 100,000 molecular weight. 10. A method of preparing a gel for carrying animal medications comprising admixing a polymer with a drug for treating a condition affecting the animal and a glycol or glycerin, optionally heating the admixture and adding in increments with agitation a fatty acid ester of glycerin.

Inventors: ZINGERMAN, JOEL R.
Applicants: MERCK & CO. INC.
Application year: 1982
Main classification: A61K9
IPC codes: A61K47