Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-05-03
2003-03-18
Acquah, Samuel A. (Department: 1711)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C264S004100, C264S004300, C264S004330, C264S004400, C264S004600, C424S460000, C424S489000, C424S492000, C428S402210, C526S065000, C526S066000, C526S071000, C514S963000, C514S965000
Reexamination Certificate
active
06534094
ABSTRACT:
FIELD OF THE INVENTION
The present application claims the benefit of Argentina Application 000102102 filed May 3, 2000 and is incorporated herein by reference thereto.
The invention is related to continuous pharmacotechnical methods for the manufacturing of microcapsules of biodegradable and biocompatible polymeric materials that incorporate an active peptide in the polymer matrix by the formation of complex emulsions of the water/oil/water type (W/O/W). The process of the invention was develop to obtain these microcapsules in sterile injectable form thus allowing for the controlled administration, for adjustable release periods of between 1 to 18 weeks, of water soluble or dispersible drugs that are used for the treatment of neoplastic, gynaecological and other diseases. Thus, the invention is in the field of pharmacology and, particularly, it relates to pharmacotechnical processes for the manufacturing of injectable, controlled release medicines.
BACKGROUND OF THE INVENTION
Since the pioneer work on encapsulation by coacervation conducted by B. K. Green (U.S. Pat. No. 2,800,457) directed to the development of copy papers, a number of publications and books have been written on microencapsulation of natural or synthetic substances into polymeric walls and their application in the controlled release of those substances (Microcapsule Processing and Technology, Asaji Kondo, 1979, Marcel Dekker). The gradual release of substances in controlled time intervals is important in pharmaceuticals drugs, foods, agrochemicals, fertilizers, and other products. A notable development, according to the number of publications observed in the recent years, took place in the area of microencapsulation of active pharmaceutical ingredients (Microspheres and Drug Therapy, Ed. Stanley S. Davis and others, 1984, Elsevier; Controlled Release Systems: Fabrication Technology, Vol I and II, Ed. Dean Hsieh, 1988, CRC Press, Inc.; Polymeric Drugs and Drugs Delivery Systems, Ed. Richard L. Dunn, 1991, ACS Symposium Series 469; Microencapsulation of Drugs, T. L. Whateley, 1992, Harwood; and Sustained Release Injectable Products, Ed. J. Senior and M. Radomsky, Interpharm Press, Denver, Colorado, USA, 2000). This complex physicochemical process has become a specialty field on its own rights.
In the area of pharmaceutical substances, clinical studies have shown that in many cases better therapeutic or pharmacological effects can be obtained by continuous infusion of the drug than when the same drug is administered by conventional methods, either in injectable, oral or other forms. Thus, it is necessary to consider using technologies for the prolonged release of active ingredients, which also include injection, oral, and other forms to administered the drug such as subcutaneous implants.
Generally, the substitution of a slow drug release method for a conventional one produces less pronounced collateral effects. These effects correlate to drug concentration peaks in the organism that occur when the minimum required active agent concentration is exceeded. One of those prolonged release methods is the use of microcapsules of polymers containing active agents such as polypeptides, proteins, hormones, nucleotides, and chemotherapy drugs, among others. Once the microcapsules are administered to the organism, drugs may be released by diffusion through a semi permeable wall in some cases, by wall dissolution in others, or by multiple mechanisms that include mainly the biodegradation of the encapsulating polymer in the living tissues into biocompatible fractions that follow a metabolic route for absorption or elimination. These polymer biodegradation processes cause, therefore, the slow dosing of the active ingredient.
Microcapsules based on re-absorbable and/or biodegradable polymers or co-polymers, have been the subject of extended research on manufacturing materials and methods, as well as on administration routes. Currently, microcapsules are increasingly applied in the administration of biotechnology products, including water soluble, slightly soluble, or insoluble substances. There are several administration routes for this particular type of microcapsules, depending on the drug to be released. The microcapsules can be adapted to injectable administration as well as to the administration to the gastrointestinal system, nasal tissues and other access routes.
Provided they degrade into biocompatible residues, a large number of polymers with a main hydrophobic chain may be used to form the microcapsule wall. Occasionally, the polymers may require a special level of purification. Among others, generally used biodegradable polymers are: poly(d,l-lactic) acid; poly(d,l-lactic-glycolic) copolymer; poly(caprolactones); poly(hydroxybutirate); poly(orthoesters); and poly(anhydrous) as well as mixtures of these and other polymers (Polymeric Drugs and Drug Delivery Systems, Ed. Richard L. Dunn, 1991, ACS Symposium Series 469, p. 15-20).
Poly(d,l-lactic-glycolic) acid, a d,l-lactic acid and glycolic acid copolymer, generally known as PLGA, and the homopolymer of d,l-lactic acid, poly(d,l-lactic) acid, generally known as PLA, have been used since 1973 as polymers for medicine microcapsules. Among others, examples of its use are: the microencapsulation of a narcotic antagonist like naltrexone (J. H. R. Woodlnad et al., J. Med. Chem., vol 16, 897, (1973); S. E. Harrigan et al., Midl. Macromol. Monogr., vol 5 (Polym. Delivery Systems), vol 91 (1978)); of anaesthetic substances (N. Wakiyama et al., Chem. Pharm. Bull., vol 30, 3719, (1982)), and of steroids (D. L. Wise et al., J. Pharm. Pharmacol., vol 32, 399, (1980)). We can specially mention the use of PLGA 50:50 and 69:31 (mole ratio of lactic acid to glycolic acid) in the microencapsulation of nafarelin acetate, an analog of the luteinizing hormone release hormone (LH-RH) (L. M. Sanders et al., J. Pharm. Sci., vol 73, 1294-1297, (1984)). Currently, it is completely accepted the use of PLGA and PLA as biocompatible polymers that are degradable to toxically acceptable products that are eventually eliminated from the body (D. H. Lewis, Biodegradable Polymers as Drug Delivery Systems, Ed. M. Chasin et al., Marcel Dekker, New York, NY, pp 1-42, 1990).
PLA or PLGA of controlled molecular weight are obtained by polycondensation of cyclic dimers of the lactic and glycolic acids, known as lactide and glycolide. There is an extensive literature on synthesis and purification methods of PLA and PLGA with molecular weights of 25000 Daltons or less. Among direct polycondensation procedures it can be mentioned those that are carried out without a catalyst, those that use a metallic catalyst as described in, among others, U.S. Pat. Nos. 3,297,033, 3,773,919 and 3,839,297, and those that use acid catalysts such as ionic exchange resins as taught in U.S. Pat. No. 4,273,920.
Slow release microcapsules are known in the administration of hormones, antibiotics, anti-inflammatory substances, antitumoral drugs, antihypertensive drugs, antipyretics, vasodilators, antiallergic agents, and analgesics, where PLGA o PLA is the constitutive biodegradable wall material.
Of particular interest for the purpose of the present invention are microcapsules containing biologically active substances that are either water soluble or can form a suspension in an aqueous phase. Among the water soluble drugs of interest are active peptides and specially hormones. One water soluble hormone of particular interest is leuprolide acetate, which was synthesized almost simultaneously by J. A. Vilchez-Martinez et al., (Biochem. Biophys. Res. Commun. 59, 1226, (1974)) and by Fujino et al. (M. Fujino et al., Biochem. Biophys. Res. Commun. 60, 406-413, (1974)), and it is the first superactive agonist of the luteinizing hormone release hormone (LH-RH), with approximately 10 times the biological activity of LH-RH. It has been used for the treatment of hormone dependent tumors in prostate (T. W. Redding et al., Proc. Nat. Acad. Sci. USA, vol 78, 6509-6512, (1981)) and breast cancers (E. S. Johnson et al., Science, vol. 194, 329-330, (
Iturraspe Jose
Moyano Nora
Nunez Jose Lucio
Acquah Samuel A.
Eriochem S.A.
Nelson Mullins Riley & Scarborough
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