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United States Patent (19) 11 Patent Number: 5,039,660 Leonard Et Al

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United States Patent (19) 11 Patent Number: 5,039,660 Leonard Et Al United States Patent (19) 11 Patent Number: 5,039,660 Leonard et al. (45. Date of Patent: Aug. 13, 1991 54 PARTIALLY FUSED PEPTIDE PELLET 4,667,014 5/1987 Nestor, Jr. et al. ................. 514/800 4,801,577 / 1989 Nestor, Jr. et al. ................. 54/800 75 Inventors: Robert J. Leonard, Lynnfield, Mass.; S. Mitchell Harman, Ellicott City, Primary Examiner-Lester L. Lee Md. Attorney, Agent, or Firm-Wolf, Greenfield & Sacks 73 Assignee: Endocon, Inc., South Walpole, Mass. (57) ABSTRACT 21 Appl. No.: 163,328 A bioerodible pellet capable of administering an even 22 Filed: Mar. 2, 1988 and continuous dose of a peptide over a period of up to a year, when subcutaneously implanted, is provided. (51) Int. Cl’.............................................. C07K 17/08 (52 U.S.C. .......................................... 514/8; 514/12; The bioerodible implant is a partially-fused pellet, 514/14: 514/15; 514/16; 514/17; 514/18; which pellet has a peptide drug homogeneously-bound 514/19; 514/800 in a matrix of a melted and recrystallized, nonpolymer Field of Search ................... 514/8, 12, 14, 15, 16, carrier. Preferably, the nonpolymer carrier is a steroid (58) and in particular is cholesterol or a cholesterol deriva 514/17, 18, 19, 800 tive. In one embodiment, the peptide drug is growth (56) References Cited hormone-releasing hormone. A method for making the U.S. PATENT DOCUMENTS bioerodible pellet also is provided. 4,164,560 8/1979 Folkman et al. .................... 424/427 '4,591,496 5/1986 Cohen et al. .......................... 424/78 13 Claims, 4 Drawing Sheets U.S. Patent Aug. 13, 1991 Sheet 1 of 4 5,039,660 U.S. Patent Aug. 13, 1991 Sheet 2 of 4 5,039,660 31%. 2 ZAZEZ 24 U.S. Patent Aug. 13, 1991 Sheet 3 of 4 5,039,660 3A 24 49 - 47 N 5 22 %if: N 22 30- -ie U.S. Patent Aug. 13, 1991 Sheet 4 of 4 5,039,660 27 AAAAZZAV // /60 (7 2 4 6 A (0. A /4 / / 20 22 AAYS (A/WBAV/0/ FWG WO 5,039,660 2 Alternatively, there are those diffusional capsules PARTIALLY FUSED PEPTIDE PELLET which rely on the seeping out of drug through the inter stices of the polymer structure. With the exception of a This invention relates generally to drug delivery few peptides of comparatively low molecular weights systems and particularly to a bioerodible pellet capable 5 (such as luteinizing hormone-releasing hormone), pep of delivering a peptide when implanted subcutaneously. tide molecules of physiologic interest have been shown to be too large to escape these capsules. BACKGROUND OF THE INVENTION Difficulties with polymer-based delivery systems also Since the elucidation of the clinical significance of may arise from a reaction between the peptide and the certain naturally-occurring peptides and the develop 10 hydrolized by product of the polymer or some additive ment of various techniques for their synthesis, it has used as a wetting agent, or a confluence of such circum become clear that these substances will be clinically stances. Conversely, the known monolithic polymer practical only if a convenient method for delivering systems exhibit a bulk erosion, thus releasing too much them in controlled doses can be provided. Because (or all) of the drug and cannot be relied upon to provide peptides are destroyed in the digestive tract when taken 15 appropriate release kinetics over long periods of time. orally, they must be administered parenterally. Further Nonpolymer-based devices have also been used as more, therapies involving bioactive peptides often de subcutaneous implants for delivering a drug. Initially, mand injections at regular intervals for extended peri pellets formed by compressing mixtures of a drug and ods of time. In view of these limitations, certain con an excipient were attempted. Such pellets, however, trolled release drug delivery systems for providing con 20 tended to disintegrate after a short time and thus exhib tinuous parenteral dosing of peptides have been sought. ited an undesirable burst effect of the active ingredient While continuous infusion systems such as pumps have and short duration of action. Later, pellets formed by been used, they are cumbersome, expensive and not "fusing', rather than compressing, mixtures of a drug completely practical. and an excipient were attempted. In particular, fused Efforts have been made to employ existing drug de 25 pellets for the controlled release of steroid hormones livery systems based on biodegradable polymers as were made by melting a mixture of cholesterol and a subcutaneous implants for the controlled release of steroidal hormone under strictly controlled conditions. peptides. Current polymer-based systems are typically The completely melted ixture would be allowed to cool combined with a drug in one of the following ways: (1) and recrystallize. It has been determined that such a Diffusion systems in which a reservoir of drug is con 30 fused pellet, if properly manufactured, releases steroidal tained in a polymer capsule and drug delivery is by the hormones in a relatively even and continuous manner slow diffusion of the drug through the interstices of the over a period of a year or more. It is believed that diffu polymer capsule wall; (2) matrix erosional systems sion is minimized in such pellets, if existent at all. (monolithic systems) in which a drug is evenly distrib 35 Rather, the uniform release rate is due to the slow sur uted in a polymer matrix and is released as the polymer face erosion of the pellet, the active ingredient being breaks down in biological fluid; and (3) diffusion/ero evenly distributed across the surface of the pellet and sion systems in which drug release occurs as a result of uniformly throughout its volume. diffusion of the drug through the polymer matrix and Fused implants have never been used as a system for release of the drug as the surface of the device continu delivering peptides. In the totally-fused pellet, the hard, ally erodes. final matrix is arrived at by the creation of a complete Numerous difficulties associated with achieving the melt that recrystallizes during cooling. This is not possi release of peptides from polymer systems have been ble with a peptide molecule which, if melted, may frag encountered in the laboratory. While these difficulties ment and lose its bioactivity. are acknowledged, they are not well understood and 45 The present invention provides a simple, inexpensive, may be the result of several physiochemical events nonpolymer, erodible pellet for subcutaneous implanta acting in concert. For example, certain peptides tend to tion providing continuous parenteral release of pep aggregate-perhaps due to ionization-under condi tides. The present invention also provides a method and tions where high concentrations of the peptides come apparatus for the preparation of such bioerodible pel into contact with phosphate buffered physiologic saline 50 lets. solution used to simulate the extracellular environment the implant will be in. This effect has proven to be a SUMMARY OF THE INVENTION significant obstacle in the development of diffusion type A bioerodible pellet capable of administering an even polymer devices. So-called aggregation is particularly and continuous dose cf a peptide over a period of up to likely in the case of selectively porous polymer cap 55 a year when subcutaneously implanted is provided. The sules. These capsules present a synthetic diffusion layer bioerodible implant is a partially fused pellet, which having pores of specific size and frequency whereby pellet has a peptide drug homogenously bound in a biological fluids first seep into the capsule, dissolve the matrix of a melted and recrystallized, nonpolymer car encapsulated drug and then carry the drug back out to rier. The carrier is bioerodable, highly crystalline and a saturated reservoir (formed by the normal reaction of 60 lipophilic. subcutaneous fibrous tissue to the presence of the cap The partially fused pellet is made by forming a ho sule) surrounding the implant. In such systems, depend mogenous mixture of a bioerodible nonpolymer carrier ing on the net charge of the molecule and the size of the and a peptide, the carrier having a lower melting tem pores (dictated by the size of the molecule), enough perature than the peptide. The mixture is then heated to biological fluid will enter the capsule to reach a critical 65 a temperature to cause the carrier to melt, but not so point at which aggregation takes place and the drug high as to cause the peptide to melt or degrade. Thus a assumes the consistency of a thick gel that resists diffu partially-melted solution is formed, substantially all of sion from the capsule. the carrier being melted and substantially all of the 5,039,660 3 4. peptide not melted. Then, the partially-melted solution FIG. 4 is a cross sectional view of FIG. 1 along line is allowed to cool into a hardened pellet. 4-4 and illustrates the paste-drying Step; Most preferably the carrier is a sterol (i.e., cholesterol FIG. 5 shows the device of FIG. 4 with the top plate or a cholesterol derivative or an ester thereof). Non and top filter removed during the chamber-plugging sterol carriers having properties similar to the foregoing 5 step; sterols when melted, recrystallized and implanted in the FIG. 6 illustrates the pin block used during the com body may be substituted. The peptide drug may be any pression step; bioactive peptide, and according to one preferred em FIG. 7 is a cross sectional representation of an appa bodiment, is growth hormone-releasing hormone ratus according to the invention during the compression (GHRH). The peptide and carrier must be selected such 10 step; that the peptide will not melt, degrade or otherwise lose FIG.
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