Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1998-07-27
2002-08-27
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S426000
Reexamination Certificate
active
06440460
ABSTRACT:
The present invention relates to a pharmaceutical composition for the controlled release of therapeutic agents from carboxylic acid ortho ester polymers and to a process for the preparation of said pharmaceutical compositions.
BACKGROUND OF THE INVENTION
Carboxylic acid ortho ester polymers consisting essentially of monomer repeating units of the partial formula
wherein R
1
represents hydrogen or C
1-4
-alkyl and A represents a hydrocarbon chain of the formula
wherein R
a
, R
b
und R
c
independently of one another represent hydrogen or C
1-4
-alkyl, and m and n independently of one another represent zero or integers from one to three; methods for preparing such ortho esters and their utility as carriers in so-called controlled release pharmaceutical compositions have been disclosed in Published International Patent Application (WO) 91/03510, International Publication Date: Aug. 23, 1990.
The slow hydrolysis of these carboxylic acid ortho ester polymers and the controlled release of therapeutic agents from the polymer matrix has been disclosed in Published International Patent Application (WO) 93/00383, International Publication Date: Jun. 18, 1992. Under physiologically acceptable conditions of pH 7.4, the hydrolysis of the ortho ester polymer (1) has been observed. This hydrolysis could formally be regarded as the reversal of the polymerisation step, whereupon a triol of the formula
is generated and the acid R
1
—COOH is being liberated. When an carboxylic acid ortho ester polymer consisting essentially of monomer repeating units of the partial formula
is hydrolyzed, the acid CH
3
COOH is liberated. Upon progressive hydrolysis of the ortho ester polymers, an increasing amount of carboxylic acids R
1
COOH is being liberated. This causes a decrease of the pH-level in-vitro from values of about 6.5 to 4.5 to even lower values in 1-5 days depending on the moleclur weight of the polymer.
This decreasing pH-level renders pharmaceutical compositions or administration systems containing the above-mentioned carboxylic acid ester ortho ester polymers less feasible for various types of administration, especially intramuscular, subcutaneous and intraocular administration, since it has firmly been established that the injection of a formulation with an acidic pH could trigger inflammation, cf. Sekizawa et at.,
J. Toxicol. Sci.
19, 25-35 (1994),
The addition of a base to achieve neutralization is deemed unsuitable, since basic substances produce a local pH level above 8 at the site of addition. This is not acceptable for implants and for various modes of administration, especially intravenous and intraocular administration.
OBJECTS OF THE INVENTION
Accordingly, the problem to which the present invention relates may be defined as follows: It is desirable to provide a pharmaceutical dosage form for the controlled release of active agents from carboxylic acid ortho ester polymers. To solve this problem, it is necessary to maintain the pH-level in a physiologically acceptable constant range between 5.0 and 7.5.
This problem has been solved by adding a pharmaceutically acceptable salt of an acid, which together with the acid being liberated from the decomposition of the carboxylic acid ortho ester polymer (I) forms a buffer system in a physiologically acceptable pH-range.
GENERAL DESCRIPTION OF THE INVENTION
The present invention, therefore, relates to a pharmaceutical composition for the controlled release of therapeutic agents from a polymer comprising:
a) the therapeutic agent or a combination of therapeutic agents to be administered;
b) a bioerodible carboxylic acid ortho ester polymer consisting essentially of monomer repeating units of the partial formula
wherein R
1
represents hydrogen or C
1-4
-alkyl, and A represents a hydrocarbon chain of the formula
wherein R
a
, R
b
und R
c
independently of one another represent hydrogen or C
1-4
-alkyl, and m and n independently of one another represent zero or integers from one to three;
c) a pharmaceutically acceptable salt of an acid, which together with the acid R
1
—COOH being liberated from the decomposition of the carboxylic acid ortho ester polymer (I) forms a buffer system in a physiologically acceptable pH-range; and the following optional components:
d) further pharmaceutically acceptable additives; and/or
e) a pharmaceutically acceptable carrier liquid.
The pharmaceutical composition is suitable for implants and also for various types of administration, especially parenteral administration by injection, e.g. intramuscular, subcutaneous, subconjunctival, intraocular or periodental administration. The controlled release of the active agent administered follows an approximate “zero order” pattern (constant amounts of active agent are released within defined time periods). The decomposition products of the polyortho esters defined above are physiologically acceptable and no removal of undesirable decomposition products from the site of administration is deemed necessary.
The general terms used throughout the specification of this invention are preferably defined as follows:
The term pharmaceutical composition defines a mixture containing the therapeutic agent or combination of therapeutic agents to be administered in the selected dosage form to a host in a therapeutic method of treating the disease or condition indicated. Intramuscular and intraocular administration of the pharmaceutical composition are particularly preferred.
Component a)
The term therapeutic agent as used herein is intended to define a compound or composition of matter which, when administered to a human being or an animal, induces a desired pharmacological and/or physiological effect by local and/or systemic action. In general, this term includes therapeutic or prophylactic agents in all major therapeutic/ prophylactic areas of medicine. Suitable therapeutic agents include the following pharmaceutical agents: antiinflammatory agents, for example dexamethasone, sodium dexamethasone sulfate, hydrocortisone or prednisolone, coronary dilators, for example nifedipine, isosorbitol dinitrate, nitroglycerine, diltiazem, trapidil, dipyridamole or dilazep, prostaglandins, for example prostaglandin E
1
, E
2
or F
2A
, peripheral vasodilators, for example ifenprodil, cinepazet maleate, cyclandelate, cinnarizine or pentoxyphylline, antibiotics, for example ampicillin, amoxycillin, cephalexin, cephradine, cefroxadin, cefaclor, erythromycin, bacampicillin, minocycline or chloramphenicol, antispasmodics, for example propantheline, atropine or scopolamine, antitussives and antiasthmatics, for example theophylline, aminophylline, methylephedrine, procatechol, trimethoquinol, codeine, clofedanolol or dextromethorphan, diuretics, for example furosemide or acetazolamide, muscle relaxants, for example chlorphenesin carbamate, tolperison, eperison or baclofen, mild tranquilisers, for example oxazolam, diazepam, clotiazepam, medazepam, temazepam or fludiazepam, potent tranquilisers, for example sulpiride, clocapramine or zotepin, beta-blockers, for example pindolol, propranolol, carteolol, oxprenolol, metoprolol or labetalol, antiarrhythmics, for example procainamide, disopyramide, ajimalin or quinidine, antigout agents, such as allopurinol, anticoagulants, such as ticlopidine, antiepileptics, for example phenytoin or valproat, antihistamines, for example chlorpheniramine, clemastine, mequitazine, alimemazine, cyproheptadine, agents for treating nausea and dizziness, for example diphenidol, methochlopromide, domperidone or betahistine, antihypertensives, for example reserpine, rescinnamine, methyldopa, prazosin, clonidine or budralazin, sympathomimetics, for example dihydroergotamine, isoproterenol or etilefrin, expectorants, for example bromhexine, carbocisteine, L-ethylcysteine or L-methylcysteine, oral antidiabetics, for example glibenclamide or tolbutamide, cardiovascular agents, for example ubidecarenon or adenosine.
Therapeutic agents can be converted into pharmaceutically acceptable salts, for example into a hydrobromide, hydrochloride, mesylate, acetate, succinate,
Gurny Robert
Tabatabay Cyrus
Zignani Monia
Allergan Sales Inc.
Baran Robert J.
Fisher Carlos A.
Voet Martin A.
Webman Edward J.
LandOfFree
Pharmaceutical compositions containing buffered ortho ester... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutical compositions containing buffered ortho ester..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical compositions containing buffered ortho ester... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2895855