Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1998-01-05
2002-02-12
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S493000
Reexamination Certificate
active
06346274
ABSTRACT:
The present invention concerns parenteral pharmaceutical forms of administration in the form of microparticles (MP) for the controlled release of polypeptides and a process for the production of these microparticles.
As a result of the rapid advance of developments in biotechnology, numerous bioactive macromolecules are available in an adequate quantity for clinical application. Due to their structure they are hydrolytically cleaved in the gastro-intestinal tract and can therefore only be administered parenterally. Since they have a short half-life it is useful to develop parenteral depot systems in order to reduce the frequency of injections and to achieve a constant blood level.
A number of depot systems, in particular micro-particulate systems, have been described in the technical and patent literature which release physiologically active substances after parenteral administration as constantly as possible over a relatively long period of time. In this connection it should be noted that proteins in comparison to low molecular substances have specific characteristics due to their complex structure, their high molecular weight and the low degree of loading that is necessary due to their high biological efficacy which make it difficult to microencapsulate them successfully. Hence depending on the type of microencapsulation method used the protein stability can be adversely affected and the release may not be optimal or there may be an unsatisfactory release profile. The release behaviour is influenced on the one hand by the high molecular weight and the hydrophilic structure but also on the other hand by stability problems (including aggregation) of the protein and the low degree of loading.
One of the most important production methods for microparticles such as for example microcapsules or microbeads is the so-called triple emulsion process which has already been used for the microencapsulation of proteins. Basically in this method, which is also referred to as the W/O/W technique, the active substance is dissolved or suspended in an aqueous solution and this aqueous solution is homogenized with an oily solution of an organic water-immiscible solvent containing a polymer to form a W/O emulsion. This W/O emulsion is dispersed in a solution containing an aqueous stabilizer (external aqueous phase) so that an emulsion with three phases (triple emulsion) is formed. The solvent is then evaporated by various techniques which results in a hardening of the microparticles. The hardened microparticles are collected by centrifugation and/or filtration and, after washing with water or suitable aqueous solvents, dried by lyophilization or vacuum drying at room temperature. The polymers that are usually used are polymers of lactic acid (LA=lactic acid) and glycolic acid (GA=glycolic acid) or copolymers thereof (PLGA) with molecular weights between 2,000 and 100,000 and a ratio of lactic acid to glycolic acid between 100:0 to 50:50.
The residual content of solvent in the microparticles may prove to be problematic when using the triple emulsion method (R. Jalil and J. R. Nixon, J. Microencapsulation 7 (3), 1990, p. 297-325) since the dichloromethane which is used most frequently as the polymer solvent appears to be critical from a toxicological point of view. The residual content of solvent should also be kept as small as possible due to its potential influence on the polymer properties and the stability of the active substance in the polymer matrix.
The production of microcapsules with the aid of the triple emulsion method is disclosed for example in the European Patent Application EP 0 145 240 (Takeda) wherein the inner aqueous phase has a viscosity of at least 5,000 mPas or is completely solidified. The viscosity is increased by auxiliary substances such as gelatin, human serum albumin, globulin, casein, collagen and polyamino acids. The microencapsulation of &ggr; interferon and heparin is described in application examples.
The same production process is described in the Patent document EP 0 190 833 (Takeda) except that in this case the viscosity of the W/O emulsion is set at a value between 150-10,000 mPas. This is achieved by varying the polymer concentration (PLGA 100/0−50/50) and by adding natural or synthetic high molecular compounds such as e.g. proteins, carbohydrates (cellulose, dextrin, pectin, starch, agar), polyvinyl compounds, polycarboxylic acids or polyethylene compounds to the aqueous phase. This is intended to greatly reduce the tendency of the microparticles to aggregate and cohere during their production. In one application example interferon alpha is encapsulated.
In EP 0 442 671 (Takeda) similar statements to those in EP 0 190 833 are made with regard to aggregation properties, spherical shape of the microparticles and potential additives. According to the patent document “substances retaining the medicinal substance” are not absolutely necessary. The examples that are specifically disclosed and elucidated in more detail in the description relate to the short chained and relatively stable peptide TAP144 which is an LHRH analogue.
Examples of the microencapsulation of peptides and proteins with the aid of the W/O/W technique are also published in the technical literature.
Thus Ogawa et al., (Chem. Pharm. Bull. 1988, vol. 36, No. 3, p. 1095-1103) describe the microencapsulation of leuprorelin acetate, a peptide, using PLA (polymer of lactic acid) and PLGA and also elaborate on the release behaviour of the peptide.
Cohen et al., (Pharmaceutical Research 1991, vol. 8, No. 6, p. 713) encapsulated FITC horseradish peroxidase and FITC-BSA in PLGA microparticles with a molecular weight of 14,000 or less and a ratio of lactic acid/glycolic acid of 75/25 and found that the protein BSA was undamaged and that the enzyme activity was preserved. Jeffery H et al. (Pharmaceutical Research 1993, vol. 10, No. 3, p. 362) used ovalbumin as the core material and were able to demonstrate the intactness of the released protein. M. S. Hora et al., (Biotechnology 1990, vol. 8, p. 755) used interleukin 2 and modified forms thereof as the core material and examined the release behaviour of PLGA microparticles which contained human serum albumin as an excipient.
In addition various processes for the production of microparticles based on PLA or PLGA polymers and the influence of additives on the protein stability were examined in more detail in various publications based on model substances for proteins (cf. W. Lu and G. Park, PDA Journal of Pharmaceutical Science & Technology, 1995, 49: 13-19; M.-K. Yeh et al., Journal of Controlled Release, 1995, 33: 437-445; M. J. Alonso et al., Vaccine, 1995, 12: 299-306; J. P. McGee et al., Journal of Controlled Release, 1995, 34: 77-86). Ovalbumin, tetanus toxoid and carboanhydrase were used in these cases as model proteins.
Youxin L. et al. (Journal of Controlled Release 32, (1994) 121-128) describe depot forms of ABA triblock copolymers (MW: 15,000-40,000) the A block of which is a copolymer of lactic acid and glycolic acid and the B block of which is a polyethylene glycol chain (PEG). They found that these microparticles rapidly and continuously released bovine serum albumin over 2-3 weeks which is relatively insensitive to aggregation and was used as a model protein at a high degree of loading (ca. 3-4% w/w) (polymer composition LA:GA:PEG=48:14:38 [mol %]).
The PLGA polymers that have up to now often been used to produce microcapsules have the major disadvantage of a low swelling capability due to their hydrophobic properties as a result of which water can only slowly enter into the interior of the depot form. This impedes the diffusion of the protein molecules through the polymer layers which results in an unsatisfactory release rate. This is especially the case when very small amounts of polypeptide are included in the microparticles i.e. at a low degree of loading. Furthermore the slow uptake of water results in a high local protein concentration due to the small amount of water that is available which promotes t
Kissel Thomas
Koll Hans
Morlock Michael
Winter Gerhard
Arent Fox Kintner & Plotkin & Kahn, PLLC
Roche Diagnostics GmbH
Webman Edward J.
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