Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Aftertreated solid synthetic organic polymer
Reexamination Certificate
1998-06-03
2002-03-05
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Aftertreated solid synthetic organic polymer
C514S772700, C528S357000
Reexamination Certificate
active
06353030
ABSTRACT:
This invention relates to polylactides in a purified state, to the method of their purification and to pharmaceutical compositions comprising the purified polylactides.
The European Patent Application No. 0270987 A2 describes polylactides, e.g. polylactide-co-glycolides, which have been prepared by condensation of lactic acid and glycolic acid or preferably by polymerisation of lactide and glycolide in the presence of a catalyst, e.g. tin di-(2-ethyl hexanoate), also known as tin octoate or tin octanoate.
The polylactides are purified by dissolving them in a solvent, which is not or is only partially miscible with water, e.g. methylene chloride, and washing the solution with an aqueous solution of an acid, e.g. HCl or of a metal ion complexing agent e.g. EDTA, after which the catalyst metal cation or its complex is transferred to the aqueous solution, in which it is better soluble.
However, after separation and isolation of the organic solvent layer and the precipitation of the polylactide from it e.g. by mixing the layer with an organic solvent, e.g. petrol ether or an alcohol, e.g. methanol, which dislodges the polylactide from the solution, the precipitated polylactide still contains a certain amount of the catalyst metal cation—about 2 ppm—and additionally the catalyst anion, e.g. in acid form. Further the polylactide contains a certain amount of brown coloured decomposition by-products which have been formed in the polymer preparation process, especially under the influence of the catalyst.
Since polylactides, e.g. polylactide-co-glycolides, are preferably used as matrices for drug compounds e.g. in implants or microparticles, which are administered parenterally, the remaining impurities can give rise to local irritation reactions of the body tissue and, e.g. depending on the catalyst type, to an instability of the matrix and thus possibly to an accelerated drug compound release. The brown impurities and the catalyst should thus preferably be removed as good as possible.
Catalyst-free polylactides on the basis of the condensation of lactid acid and optionally glycolic acid are known, but have low molecular weights of about 2000 to 4000.
Polylactides of a higher molecular weight are preferred and can only be made in the presence of a catalyst.
According to the European Patent No 0026599 B1 lactic acid and glycolic acid were reacted in the presence of a strong acid ion-exchange resin as a catalyst, which after the reaction could be removed from the copolymer product by filtering the molten reaction mixture or by cooling the reaction mixture, dissolving the copolymer in an organic solvent in which the ion-exchange resin is insoluble, filtering the solution and removing the organic solvent after which a copolymer was obtained from which the solid phase catalyst was removed to a substantially extent.
However, by this method only polylactides were obtained having a molecular weight of from about 6000 to 35000.
Polylactides, e.g. polylactide-co-glycolides, having a broader molecular weight range than up to 35000 are preferably made by using lactide and optionally e.g. glycolide as monomers, but are polymerised in the presence of a metal catalyst, which reaction type, as has been discussed before, leads to a considerable contamination of the reaction product.
We have found now, that polylactides, e.g. polylactide-co-glycolides, especially those prepared from lactide and glycolide as monomers, can be obtained in a better purified state. The invention provides a polylactide in a purified state which meets the requirements of
the colour strengths of reference solutions B
2
-B
9
of the brown colour test of the European Pharmacopoeia, 2nd Edition (1980), part I, Section V, 6.2. and
containing one or more metals in cationic form, the metal ion(s) having a concentration of at most 10 ppm.
The polylactide preferably has the reduced colour strengths of the reference solutions B
4
-B
9
, especially of reference solution B
9
. The colour of a reference solution B
9
indicates that the polylactide is an off-white or colourless product.
The polylactides which are preferably prepared contain particularly bivalent metal ions, like Zn
++
and especially Sn
++
.
For the determination of the tin amount, the polymer is decomposed under high pressure with a mixture of hydrochloric acid and nitric acid. The precipitation and concentration of tin from that mixture occurs on a membrane filter and the measurement of the metal amount is carried out by energy dispersive X-ray fluorescence (EDXRF), as described by H. D. Seltner, H. R. Lindner and B. Schreiber, Intern. J. Environ. Anal. Chem., 1981, Vol. 10, pp. 7-12 supplemented with a reference graphite furnace atomic absorption spectrometry method, as discussed on the 6th Colloquim Atomspektrometrische Spurenanalytik, Apr. 8-12th, 1991 in Konstanz, Germany, Authors: H. Seltner, G. Hermann and C. Heppler.
According to the invention the concentration of Sn
++
in the purified polyactide of the invention is preferably at most 1.5 ppm, particularly at most 1 ppm; the catalyst anion is preferably ethyl-hexanoate, which is in the purified polylactide of the invention preferably present in a concentration of at most 0.5% by weight of the polylactide.
The purified polylactide preferably contains apart from its lactide units further structural units e.g. such as described in the european Patent Application No 0270987, second passage on page 4, of which the glycolide unit is the preferred unit since, depending on its monomer ratio in the polymer chain, it can shorten the decomposition period of the polymer in the body and thus accelerate the drug compound release time. The glycolide unit is, as is known, the most frequently used additional unit in polylactides.
The monomer molar ratio's of the lactide/glycolide units in the purified polymers according to the invention are preferably 100-25/0-75, particularly 75-25/25-75, especially 60-40/40-60, more especially 55-45/45-55, e.g. 55-50/45-50.
It is known that the polymerisation reaction of monomers like lactide and glycolide is preferably carried out in the presence of a compound having one or more hydroxylgroups, which functions as a starter in building up a linear polymer chain. Known starters are e.g. lactic acid and glycolid acid. Other hydroxyl group containing compounds can also be used, e.g. alcohols. The starters are in fact used to control the chain length of the polylactides. A smaller amount of starting hydroxyl compound leads to longer chains than greater amounts. Excellent regulators are polyols, e.g. those described in the UK Patent Application GB 2.145.422A, of which mannitol and especially glucose are the most preferred.
By using this type of starting compounds relatively high molecular weight hard polylactide-co-glycolide materials can be obtained, which are very suitable as implants or microparticle materials, and have 2 or 3, preferably more than 3, e.g. 4 relatively short polylactide-co-glycolide chains and can hydrolyse in the body tissues within a relatively short drug release period of some weeks to e.g. 2 months or more, preferably within 4-6, e.g. 5 weeks. Although according to the invention the purified polylactides can have a linear structure, the preferred purified polylactides according to the invention are those having the structure described in the GB Patent 2.145.422 A, being esters of a polyol containing at least 3 hydroxyl groups, preferably those being an ester of a sugar or a sugar alcohol, especially an ester of glucose. They are star shaped, having a centre of e.g. the glucose rest and rays of linear polylactide chains.
After their preparation the star polymers are, more than the linear polymers, contaminated by brown-coloured by-products, since the sugar or sugar alcohol, used for their preparation, is also be partially decomposed by the catalyst. The star polymers have monomer molar ratios of lactid/glycolide units which are preferably those, indicated above for the linear polymers.
The star polymers have preferably a mean molecule weight M
Novartis AG
Pfeiffer Hesna J.
Webman Edward J.
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