United States Patent (19) 11 Patent Number: 4,765,973 Heller 45 Date of Patent: Aug. 23, 1988 54) POLYMERS CONTAINING PEN DANT ACD Assistant Examiner-M. L. Moore FUNCTIONALITIES AND LABILE Attorney, Agent, or Firm-Manfred Polk; Michael C. BACKBONE BONDS Sudol (75) Inventor: Jorge Heller, Woodside, Calif. 57 ABSTRACT Assignee: Merck & Co., Inc., Rahway, N.J. The instant invention is directed to a polymer with at 73 least one labile backbone bond per repeat unit and at (21) Appl. No.: 915,348 least one pendant acid functionality per thousand repeat 22 Filed: Oct. 6, 1986 units. The instant invention is also directed to a controlled Related U.S. Application Data release device which comprises: (A) a polymer with at least one labile backbone bond (62) Division of Ser. No. 68,002, Jun. 6, 1984, Pat. No. per repeat unit and at least one pendant acid func 4,639,366. tionality per thousand repeat units; and 51 Int. Cl'.............................................. A61K 31/74. (B) a beneficial substance incorporated within or 52) U.S. C. ....................................... 424/486; 424/78 surrounded by the matrix of said polymer. (58) Field of Search ........................ 424/19, 20, 22, 78 Primary Examiner-John Kight 3 Claims, No Drawings 4,765,973 1. 2 Tri- and higher hydroxyl functional polyols may be POLYMERS CONTAINING PEN DANT ACID used, which will result in crosslinked polymers. FUNCTIONALTES AND LABLE BACKBONE Any polymer containing at least one acid labile back BONDS bone bond per repeat unit (preferably two per repeat 5 acid unit) may be used to react with the polyol contain This is a division of application Ser. No. 618,002 filed ing a pendant acid group. Examples include polyortho June 6, 1984 now U.S. Pat. No. 4,639,366. esters (including polyorthocarbonates), polyacetals, polyketals, polyesters and polyphosphazenes. The pre BACKGROUND OF THE INVENTION ferred polymers are poly(orthoesters) and polyacetals. There has long been a need in the field of drug deliv 10 Examples of polyorthoesters, polyorthocarbonates and ery devices to have a drug released in the human or polyacetals are disclosed in U.S. Pat. Nos. 4,093,709, animal tissue at the place where it is most therapeuti and 4,304,767, 4,221,779 and 4,150,108 which are cally effective and to have said drug released in the hereby incorporated by reference. tissue in a controlled manner over a long period of time. The preparation of the polymers may be by a variety U.S. Pat. Nos. 4,093,709 and 4,304,767 disclose poly 15 of methods. U.S. Pat. No. 4,093,709, column 8, line 11 mers which can be used as a matrix to contain a drug. through column 9, line 47, outlines several methods of The polymers contain labile backbone bonds which preparation. hydrolyze in the presence of water causing a controlled Any beneficial substance (e.g. therapeutics or biologi erosion of the matrix and resultant release of the drug. cally active agents) may be used in the controlled re These polymers have the disadvantage, however, that 20 lease device. The substance should not significantly they hydrolyze extremely slowly. interfere with the acid catalyzed hydrolysis of the labile The polymers of the instant invention have the ad polymer backbone bond. Basic substances may cause vantage that the pendant acid functionalities catalyze some interference. It is preferred that any acid sub the hydrolysis of the labile polymer backbone bonds. stances be in the salt form. 25 Representative examples of the polyols are as fol DESCRIPTION OF THE INVENTION lows: 9,10-dihydroxystearic acid; 3,6-dihydroxynaph The instant invention is directed to a polymer with at thalene-2,7-disulfonic acid; 2,4-dihydroxybenzoic acid; least one labile backbone bond per repeat unit and at 3,4-dihydroxycinnamic acid; 6,7-dihydroxy-2-naphtha least one pendant acid functionality per thousand repeat 30 lene sulfonic acid; 6,7-dihydroxy-2-naphtalene sulfenic units. acid; 2,5-dihydroxyphenylacetic acid; 2,4-dihydrox The instant invention is also directed to a controlled ypyrimidine-5-carboxylic acid; 4,8-dihydroxyquinoline release device which comprises: 2-carboxylic acid; and mixtures thereof. (A) a polymer with at least one labile backbone bond It will be realized that these are merely representative per repeat unit and at least one pendant acid func examples and that any polyol containing an acidic tionality per thousand repeat units; and 35 group can be used provided it does not adversely affect (B) a beneficial substance incorporated within or the polymerization reaction or leads to toxicologically surrounded by the matrix of said polymer. undesirable degradation products. Thus, any group that The polymers of the instant invention may be pre can be incorporated into the polymer and which when pared by reacting a polyol, preferably a diol, having a placed in water ionizes to produce a pH lower than pendant acidic group with a polymer containing a labile about 7.0 is a useful group provided the above limita backbone bond. Excess amounts of either component tions are met. may be used in preparing the final polymer, although The molecular weight of the polymer is not critical. stoichiometric amounts are preferred. The molecular weight is preferably at least 1,000 as U.S. Pat. Nos. 4,093,709 and 4,304,767, which are determined by low angle light scattering. hereby incorporated by reference, disclose numerous 45 Representative beneficial substances (therapeutics polyols. Any of these polyols may be modified to con and biologically active agents) for incorporation into or tain one or more pendant acidic groups per thousand to be surrounded by the polymer matrix to be used with repeat units, up to a maximum of one per repeat unit. this invention and to be released to an aqueous environ The number of acid groups incorporated depends on 50 ment include without limitation, the following: the desired rate of erosion. For increased erosion, rela 1. Protein drugs such as insulin; tively more acid groups would be incorporated. A pre 2. Desensitizing agents such as ragweed pollen anti ferred group of polyols may be represented as follows: gens, hay fever pollen antigens, dust antigen and milk antigen; 55 3. Vaccines such as smallpox, yellow fever, distem per, hog cholera, fowl pox, antivenom, scarlet fever, dyptheria toxoid, tetanus toxoid, pigeon pox, whooping cough, influenzae, rabies, mumps, measles, poliomyeli tis, Newcastle disease, etc.; 4. Anti-infectives, such as antibiotics, including peni where X is the acidic group and Y is a spacer group. R cillin, tetracycline, chlortetracycline bacitracin, nysta and Y may be an alkyl, aryl or substiuted alkyl or aryl, tin, streptomycin, neomycin, polymyxin, gramicidin, preferably containing 1 to 18 carbon atoms, most prefer oxytetracycline, chloramphenicol, and erythromycin; ably 2 to 10 carbon atoms. The Y group may optionally sulfonamides, including sulfacetamide, sulfamethizole, be eliminated. 65 sulfamethazine, sulfadiazine, sulfamerazine, and sulfi Any acidic group may be used in the polyol. Exam soxazole, cefoxitin; anti-virals including idoxuridine; ples include carboxylic, carbon acid, phosphoric, sul and other anti-infectives including nitrofurazone and fonic and sulfenic acid groups. sodium propionate; 4,765,973 3 4. 5. Antiallergenics such as antazoline, methapyrilene, nents of molecular complexes, or nonirritating, pharma chlorpheniramine, pyrilamine and prophenpyridamine; cologically acceptable salts such as hydrochloride, hy 6. Steroidal anti-inflammatory agents such as hydro drobromide, sulfate, phosphate, nitrate, borate, acetate, cortisone, cortisone, hydrocortisone acetate, dexameth maleate, tartrate, salicylate, etc. For acidic drugs, salts asone, dexamethasone 21-phosphate, fluocinolone, tri of metals, amines, or organic cations (e.g., quaternary amcinolone, medrysone, prednisolone, prednisolone ammonium) can be employed. Furthermore, simple 21-phosphate, and prednisolone acetate; derivatives of the drugs (such as ethers, esters, amides, 7. Decongestants such as phenylephrine, naphazoline, etc.) which have desirable retention and release charac and tetrahydrazoline; teristics but which are easily hydrolyzed by body pH, 8. Miotics such as pilocarpine, eserine salicylate, car 10 enzymes, etc., can be employed. bachol, diisopropyl fluorophosphate, phospholine io The amount of drug or beneficial substance incorpo dide, and demecarium bromide; rated into the polymer matrix will vary greatly depend 9. Anticholinergics such as atropine sulfate, cyclo ing on the particular drug, the desired therapeutic effect pentolate, homatropine, scopolamine, tropicamide, eu and the time span in which the polymer matrix is eroded catropine, and hydroxyamphetamine; 15 to release the particular drug. Thus, there is no critical 10. Sympathomimetics such as epinephrine; upper limit on the amount of drug incorporated in the 11. Sedatives and Hypnotics such as pentabarbital polymer matrix and the lower limit will also depend on sodium, phenobarbital, secobarbital sodium, codeine, the activity of the drug (usually at least 0.1%, prefera (a-bromoisovaleryDurea, carbromal; bly 0.1 to 30%, by weight, based on the total weight of 12. Psychic Energizers such as 3-(2-aminopropyl)in the device) and the time span for the erosion of the dole acetate, 3-(2-aminobutyl)indole acetate and ami polymer and subsequently the drug release. Thus, it is triptyline; not practical to define a range for the therapeutically 13. Tranquilizers such as reserpine, chlorpromazine, effective amount of drug to be incorporated in the novel thiopropazate and perphenazine; polymer matrixes of the instant invention. 14. Androgenic steroids such as methyltestosterone 25 Also in the case of the drug or other beneficial sub and fluorymesterone; stance incorporated into the polymer matrix as stated 15. Estrogens such as estrone, 17 g-estradiol, ethinyl above, the amount of drug or beneficial substance will estradiol, and diethyl stilbesterol; depend on the type of drug or substance for the condi 16. Progestational agents such as progesterone, tion being treated and can generally be up to 70% of the megestrol, melengestrol, chlormadinone, ethisterone, 30 polymer matrix by weight.