HU193301B - Matrix granulate and process for production thereof - Google Patents

Abstract

The prod. contains a 5:1 to 1:5 mixt. of vinyl-pyrrolidone-vinyl-acetate copolymer and an acrylic-acid polymer crosslinked with poly-allyl-saccharose, and opt. inert filler.

Description

FIELD OF THE INVENTION The present invention relates to a process for preparing combinations containing an active ingredient and an amphipathic copolymer which is biodegradable in water and self-dispersible in a water-stable dispersion for human and veterinary use. The combinations of the present invention can be used to formulate sustained release drugs.

As used herein, the term "self-dispersible" refers to copolymers which, when added to water, form a stable dispersion without the addition of any surfactant or other additive. In this context, the term "stable" refers to dispersions that do not significantly agglomerate or precipitate over time (e.g., 24 hours) to form the combination into a sustained release pharmaceutical composition.

Nos. 3,773,919 and 3,887,699. U.S. Pat. Although certain polypeptide-containing pharmaceutical formulations are mentioned in the patents, it has been found that most polypeptide-containing formulations are almost completely degraded at temperatures of at least 130 ° C, and therefore the technologies disclosed in the cited patents are not suitable for sustained release. for the preparation of pharmaceutical preparations.

No. 58,481. The copolymers disclosed in the above-mentioned European Patent Application, U.S. Patent Nos. 5,109 and 6,125, are not useful in the manufacture of pharmaceutical compositions for sustained release, even if the pharmaceutical formulation technology is modified to prevent degradation of the polypeptide-containing pharmaceutical composition. In fact, the drug release is in fact biphasic and not continuous; in the initial phase of drug delivery, the polypeptide is "leached" from the surface, followed by a "dead phase" for a prolonged period of time, with little or no release of the drug. The main phase of release of the polypeptide occurs only after this: the copolymer matrix absorbs water and as a result, the biological member Icb is degraded.

No. 58,481. EP-A-4,173,919 and EP-A-3,887,699, discloses that sufficient sustained-release polypeptide formulations can be prepared. U.S. Patent Nos. 4,119,198 and 4,660,198 generally employ lower molecular weight polylactide or poly (lactide co-glycolide) and work at lower temperatures. However, the process still requires the use of organic solvents and many polypeptides do not exhibit sufficient stability.

No. 92,918. European Patent Specification No. 4,466,011 discloses the use of suitable general type biodegradable amphipathic copolymers according to the present invention as components of sustained release pharmaceutical compositions. However, the copolymers disclosed in the cited European Patent Application do not form stable dispersions by self-dispersion in water and therefore the use of organic solvents is required. As mentioned above, organic solvents can cause the polypeptides to be denatured during the preparation of sustained release pharmaceutical compositions.

According to the invention, it is desirable to eliminate the effects of high temperature, non-neutral pH and, in the case of water-soluble active substances (e.g. polypeptides), contact with organic solvents in the manufacture of continuous release drug / polymer combinations.

It has been found that by using specific self-dispersible copolymers for the preparation of drug / copolymer combinations, or by bringing the drug / copolymer mixture into a state of self-dispersion, all of the above detrimental factors can be completely eliminated.

Some of the copolymers useful in the process of the present invention are already self-dispersible in their synthesis form, while others are not self-dispersing but tend to be self-dispersing on the inert worship.

Combinations of the self-dispersible copolymer, or made self-dispersible during the preparation of the combination, and a low molecular weight, water-insoluble active ingredient may be formulated, for example, in sustained release injection formulations. In these formulations, the self-dispersible copolymers act as highly effective dispersants, and in their presence, sustained release colloidal suspensions can be prepared from topically active compounds.

Combinations containing a self-dispersing copolymer and an active ingredient, as well as pharmaceutical formulations to be delivered specifically to certain organs of the human or animal body are useful. It is known that intravenous injection of particles or microspheres of varying size in uf, depending on the size of the particles injected, accumulates in various organs of the body [Tomlinson: "Microsoft Drug Targeting Systems for Drug Targeting and Controlled Release"; J. Int. Pharm. Techn. and Prod. Mfr. 4 (3), 49-57. (1983)). For example, particles smaller than 50nm can penetrate through the endothelial openings of the liver, and possibly localize via lymphoid transport, such as spleen, bone marrow, and possibly tumor cells. Particles of about 0.1 to 2.0 µm are rapidly cleared from the bloodstream by macrophages of the reticuloendothelial system when administered intravenously, intraarterially or intraperitoneally, and are optionally localized in the Kupfcr-scljct of the liver. For intravenous administration, 7-1? pm-ncl larger particles are mechanically screened by the lungs, while particles between 2 and 12 pm are "captured" by the capillary network of the lungs and the liver and spleen. For intra-arterial administration, particles larger than 12 µm may block the first capillary in their path. Controlled Re-23 using active ingredient / copolymer combinations of the present invention

196,301 particle size dispersions can be prepared which can be targeted to the desired organ as described above,

Some of the methods and operational steps for the preparation of drug / copolymer combinations are summarized in Flow Diagram I. For the sake of completeness, the flowcharts of the copolymer, the self-dispersible copolymer and the finished pharmaceutical compositions are shown in Figure 1.

The present invention therefore relates to a process for the preparation of a solid powdered active ingredient / copolymer combination containing up to 99% by weight of active ingredient in amphipathic, non-crosslinked, linear or non-crosslinked form for human or veterinary use, graft pen contains balloon copolymer - wherein the block copolymer comprises a hydrophobic and hydrophilic component in a weight ratio of from 1: 9 to 9: 1 and the hydrophobic component is a physiologically biodegradable or hydrolytically unstable polyhydroxycarboxylic acid polypeptide , A polyacetal of formula (I) wherein R is hydrogen or a polycarbonate or polyhloro ester of formula (II) wherein R is a hydrocarbon and n is an integer - an alternate copolymer containing the above acetal, carbonate or orthoester units alternately with alkylene diol units, a copolymer of formula (III) in which R is hydrogen and n is an integer - or two or more of the above monomers and the hydrophilic component thereof is optionally biodegradable or hydrolytically unstable polyvinyl alcohol, polyvinylpyrrolidone, poly (ethylene oxide), poly (ethylene glycol), poly (acrylic) glycol, under normal physiological conditions. amide), poly (methacrylamide), dextran, alginic acid, sodium alginate, gelatin, or a copolymer of two or more of the monomers which form the polymers listed above, by freezing the frozen stable aqueous dispersion of the copolymer and the active ingredient dried.

As used herein, the term "aqueous dispersion" includes dispersions formed with water only, and water containing a small amount (e.g., up to 10%) of water-miscible organic solvent.

Poly (hydroxycarboxylic acid) used as the hydrophobic component of the tonib copolymers used in the process of the invention include, for example, poly (D-, L- or DL-lactic acid), poly (D-, L- or DL-lactide), polyglycolic acid, polyglycolide, caprolaclone or poly (3-hydroxybutyric acid). Non-pharmacologically active hydrophobic polypeptides include, for example, apolybenzylghitamate. Polyacetals of formula (I) and polycarbonals of formula (II) or poly (ortho-ester) -ck are, for example, disclosed in U.S. Patent No. 4,093,709. The compounds disclosed in U.S. Pat. The copolymers of formula (III) may be prepared by reacting pentaerythritol with ketene and then obtaining the 3,9-bis (methylene) -2,4,8,10-tetraoxa-spiro [5,5] undecane HO-R-OH copolymerized with diols of general formula (Journal of Polymer Science, Polymer Letters, 619-624). (1980). For example, high molecular weight polyethylene glycol or a mixture of high and low molecular weight poly (c-glycol glycols) can be used as the di-formula of HO-R-OH.

Starting from water-soluble active agents (e.g. polypeptides), the above-described, self-dispersing copolymer is dispersed in water, the dispersion is buffered to a physiological or neutral pH matrix, the pufiferol dispersion is mixed with the water-soluble active ingredient / the dispersion is frozen and finally the frozen dispersion is freeze-dried.

Examples of water-soluble polypeptides include oxytocin, vasopressin, adrenocorticotropic hormone (ACTH), epidermal growth factor (EGF), transforming growth factor antagonists, prolactin, lulibcrine or lulcinizing hormone releasing hormone (LH-RH), LH-growth hormone, LH-RH, factor, insulin, somatostatin, bombesin antagonists, glucagon, interferon, gastrinl, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalinokal, endorphins, angiolensins, rcnin, bradykinin, bacilracin, their pharmaceutically active fragments, monoclonal antibodies and vaccines for vaccination.

In the case of water-insoluble active ingredients, the active ingredient is dissolved in a minimum amount of water-miscible organic solvent (e.g. dioxane, acetic acid, acetonitrile, methanol or ethanol), and the solution is added slowly with vigorous stirring. freezing the stable dispersion and finally freeze-drying the frozen dispersion.

Any low water solubility active ingredient can be used in this process.

The procedures described above in which the block copolymer is used in a self-dispersible form have been described. Certain representatives of the above-described amphipathic, non-crosslinked, linear, branched or grafted block copolymers for human or veterinary use are already self-dispersible in water during the synthesis of the copolymer. In these copolymers, the hydrophilic component is present in large amounts (greater than 50%) relative to the hydrophobic component; it also includes copolymers containing a low molecular weight hydrophobic component (e.g., an average molecular weight of less than 5000).

In addition, the structure of the copolymer, the nature of the hydrophilic and hydrophobic polymers present, control the degree of dispersion of the resulting copolymer in water.

For example, polylactide-grafted PVP containing 50% or more by weight of polyvinylpyrrolidone (hereinafter "PVP") has self-dispersing properties even though the polylactide has a relatively high molecular weight of 30,000. beyond me. Polylactide / poly (ethylene glycol 1900) is self-dispersing

196,301 (the components are present in the same weight ratio). However, polylactide / poly (ethylene glycol 5000) (weight ratio: 1: 1) can only be hardly self-dispersible. Above this molecular weight, the copolymers no longer exhibit immediate self-dispersion in water, but initially require the addition of a small amount of organic solvent, which can subsequently be removed by evaporation or freeze-drying.

If the block copolymer is formed in a non-dispersible form during synthesis, it is rendered self-dispersible by freeze-drying the frozen aqueous dispersion of the copolymer non-dispersible form.

This frozen stable aqueous dispersion is prepared by dissolving the block copolymer described above in a non-self-dispersible form obtained in the synthesis in a minimum amount of water-miscible solvent. Water-miscible solvents include low-boiling solvents (e.g., methanol or ethanol) or freeze-dried solvents (e.g., dioxane or acetic acid). The resulting solution was vigorously stirred while slowly adding excess water. The extremely fine stable aqueous dispersion formed is frozen.

However, in the process of the invention, the copolymer can be started from a non-dispersible form. This is it. Corresponds to the sequence of operations in Flow Diagram 1 where the sequence contains only one freeze-drying step. In this case, the non-self-dispersing form of the copolymer is dissolved in a water-miscible organic solvent, the copolymer is precipitated in water and water, or optionally water-miscible, optionally with a water-insoluble active ingredient. organic solvent! The resulting solution is added to the copolymer dispersion and the resulting mixture is frozen and freeze-dried. In this operation, the copolymer, which cannot self-disperse in its initial state, becomes self-dispersible during freeze-drying.

Our scope of protection extends to the production of direct precursors of self-dispersible drug / copolymer combinations, i.e. frozen aqueous dispersions containing copolymer and drug.

The copolymer / drug combinations of the present invention can be used to prepare sustained release pharmaceutical compositions. As stated above, these combinations can be converted into pharmaceutical compositions under conditions where the active ingredient is not exposed to high temperatures, a pH that is not neutral, and a high concentration of organic solvent, and is not treated with an organic solvent at elevated temperatures. The copolymer / active agent combinations can be converted into human or veterinary formulations by standard pharmaceutical practice. For example, the copolymer / drug combination is pressed at low temperatures (most of the combinations are excellent for compression at temperatures around 60 ° C, and the active ingredients, including polypeptides, which are most susceptible to thermal decomposition, have a higher decomposition point than this temperature). For example, this method can be used to produce delayed-release sustained-release implant formulations (see European Patent Nos. 58,481 and 92,918).

For example, for water-insoluble active ingredients, pharmaceutical compositions can be prepared by dispersing the copolymer / active compound combination in sterile water. This provides delayed-release sustained release formulations which can also be used as a targeted delivery to specific organs at appropriate particle size.

The particle size of the aqueous dispersion can be kept within a fairly narrow range by controlling the particle size of the polymer used. This is accomplished by making the copolymer self-dispersible form by adding water to the freeze-dried solution of the copolymer in a freeze-dried, water-miscible solvent at an appropriate rate and adjusting the stirring rate appropriately during the process. The particle size of the resulting dispersion can be measured in a conventional manner, for example using an optical microscope, a Couller counter or a nanonizer.

When the polypeptide is used as an active ingredient, low or high molecular weight, water-soluble, fully or partially water-compatible polymers (e.g., gelatin, PVP, dextran, propylene glycol, sodium alginate) are preferably used as co-exemplars for the preparation of pharmaceutical compositions. and water-soluble, synthetic, non-therapeutic polypeptides. These coexpressors create additional hydrophilic regions or pores in the polymer matrix and also stabilize the tertiary structure of the polypeptide by chain transformation; this is achieved by their full or partial compatibility with the polypeptide.

The invention is further illustrated in the following examples without limiting the scope of the invention. For the sake of completeness, the examples also describe the preparation of self-dispersible block polymers and the formulation of drug / copolymer combinations into pharmaceutical compositions.

Example 7 B-type biodegradable copolymer of type AB containing 25% by weight of 5900 molecular weight methoxy polyethylene glycol (component A) and 75% by weight poly (DL-lactide) (component B) dissolved in ice and 21 ml of distilled water was added slowly with vigorous stirring. An extremely fine dispersion is obtained. The resulting dispersion was frozen and freeze-dried at 13.3 Pa. A dried powdered copolymer is obtained. Adding the dry powder to water while stirring produces a very fine dispersion while redispersing.

Example 2

0.5 g of dry powder copolymer prepared according to Example 1 with vigorous stirring in 5 ml of 0.01% r.

Dissolve in 196,301 azide in distilled water and buffer to pH 8 with 0.1 N sodium hydroxide solution. 0.125 g of bovine serum albumin (hereinafter referred to as BSA) in 1.0 ml of distilled water, and ^I4 C-methylated BSA (10 monovalent μΙ 5 pCi / ml solution in 0.01M sodium phosphate buffer) was added. The BSA solution is added to the dispersion of the copolymer, first frozen and then freeze-dried at 13.3 Pa for 24 hours.

The freeze-dried product is formed by molding at 60-70 ° C to form 1 cm ² , 0.2 cm, 0.09 cm and 0.04 cm thick plates, respectively. Plates of different sizes were immersed in phosphate buffered sodium chloride (pH 7.4) containing 2 ml of 0.02% sodium azidol at 37 ° C. From time to time, the medium is removed, replaced with fresh buffer, and radioactivity released into the removed medium is measured. The results obtained are summarized in Table I below.

Table I

Cumulative BSA% released

Time 0.2 cm plate 0.09 '' sheet 0.04 cm plate 1 hour 10.8 23.8 46.6 4 o'clock 23.4 48.5 77.3 24 hours 64.4 86.5 86.7 3 days 86.4 92.2 88.8 12 days 90.1 92.3 90.9

Example 3

2.5 g of poly (DL-lactide-co-glycolide) - grafted PVP copolymer (containing 50% by weight of poly (D-lactide-co-glycolide) and 50% by weight of PVP); glycolide in equimolar proportions) is dissolved in 5 ml of glacial acetic acid and 20 ml of distilled water are slowly added with vigorous stirring. The resulting fine dispersion was frozen and freeze-dried at 13.3 Pa for 24 hours. A dry, powdery copolymer is obtained.

The dry powder copolymer thus obtained is re-dispersed almost immediately upon stirring with water and forms a very fine dispersion.

Example 4

Contains 2.0 g of an ABA-type biodegradable block copolymer (80 wt% poly / DL lactide) (component A) and 20 wt% poly (ethylene glycol) -1, molecular weight 2000 (component B). Add 3 ml of anhydrous ethanol and slowly add 1.5 ml of water with vigorous stirring. To the extremely fine dispersion formed, additional 15 ml of water was added with vigorous stirring, and the resulting dilute dispersion of the copolymer was buffered to pH 8 by addition of 0.1 N sodium hydroxide solution.

Dissolve 0.5 g of bovine serum albumin (hereinafter referred to as "BSA") in 5 ml of water and add ¹⁴ C-methylated BSA (70 μΙ at 5 pCi / ml in 0.01 M sodium phosphate solution). The BSA solution was mixed with the copolymer dispersion, frozen and freeze-dried at 13.3 Pa for 30 hours.

The freeze-dried powder is formed by casting at 60 ° C into sheets having a surface area of 1 cm ² and thicknesses of 0.36 cm, 0.16 cm and 0.06 cm. Sheets of different sizes at 3.7 ° C each with 2 ml phosphate buffer! (pH 7.4) was immersed in sodium chloride solution. The medium is removed at regular intervals, replaced with fresh buffer, and the radioactivity of the removed buffer is measured.

The results obtained are shown in Table II. in Table.

II. spreadsheet

Cumulative BSA% released ^{* 5}

Time 0.36 cm plate 0.16 cm plate 0.06 cm plate 1 hour 8.5 12.8 23.8 4 o'clock 17.0 28.0 58.4 24 hours 40.3 58.2 87.2 4 days 65.8 82.0 96.0 11 days 82.1 96.0 100

Example 5 g Purified methoxy poly (ethylene glycol) (molecular weight: 1900) was dried at 160 ° C for 1 hour and then with stirring under nitrogen atmosphere at 160 ° C for 10 g. lactide and 50 μΐ of stannooctoate (tin (II) -2-ethylhexanoate) were added and the mixture was heated at 160 ° C for 3 hours. On cooling, a viscous, slightly viscous liquid that solidifies is obtained. The solid product (0.5 g) was added to ml of distilled water and stirred at 37 ° C for 18 hours. An extremely fine dispersion or colloidal suspension is formed which is very transparent and exhibits a very slight haze of bluish glow only when viewed towards the light.

In contrast, a simple mixture of 0.25 g of the above methoxy-poly (ethylene glycol) and 0.25 g of poly (DL-lactic acid) does not disperse at all when mixed with 5 in 1 of water at 37 ° C, but remains in the form of a semi-solid, .

Example 6

A block copolymer of poly (DL-lactide) and methoxy-poly (cytylene glycol) (containing 50% by weight of polyester and 50% by weight of profile) is prepared by DL-lactide in the presence of methoxy-poly (ethylene glycol). 160 ° C in the presence of a tin organic catalyst is subjected to ring-opening polymerization. 100 mg

196 301 block copolymer and 10 mg of anti-estrogen (ICI 189 150; very slightly soluble in water) are dissolved in 0.4 ml of glacial acetic acid and 2 ml of water are added slowly with vigorous stirring. The drug-polymer mixture was obtained as a colloidal suspension in acetic acid-water mixture, which was frozen and freeze-dried at 13.3 Pa for 24 hours. A solid freeze-dried product is obtained.

Upon addition of 0.9% aqueous sodium chloride solution, the freeze-dried product is redispersed to give a stable aqueous dispersion for injection.

Claims (4)

Claims I. A process for preparing a solid powdered drug / copolymer combination containing up to 99% by weight of active ingredient, capable of self-dispersing, for human or veterinary use, of an average amphipalic, non-crosslinked, linear, branched or branched solids having a molecular weight of at least 1000 comprising - wherein the block copolymer comprises a hydrophobic and hydrophilic component in a weight ratio of from 1: 9 to 9: 1, and the hydrophobic component is a physiologically biodegradable or hydrolytically unstable polyhydroxycarboxylic acid, non-curative hydrophobic polypeptide of formula (I) polyacetal, where R is hydrocarbon and n is an integer, polycarbonate or poly (orthoester) of formula II, wherein R is hydrocarbon and n is an integer, the above acetal, carbon an alternate copolymer of alternating or orthoester units with alkylene diol units, a copolymer of the formula (III) wherein R is hydrogen and n is an integer, or a hydrophilic component formed by copolymerization of two or more monomers forming one of the abovementioned polymers and, under normal physiological conditions, optionally biodegradable or hydrolytically unstable polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, polyethylene glycol, polyacrylamide, poly ( methacrylamide) copolymer with dextran atginsav, sodium alginate, gelatin, or two or forming more polymers listed above ⁰ monomer copolymerization -, characterized in that the copolymer and the active agent a frozen, stable aqueous dispersion was freeze dried. 2. A process for the copolymer and water-soluble physiologically active parent frozen, stable aqueous dispersion containing ⁰ got preparation, characterized in that a defined in claim 1, the self-dispersible copolymer is dispersed in water, the dispersion After buffering to pH 15 or neutral, the buffered dispersion is mixed with an aqueous solution of the water-soluble active ingredient and the resulting copolymer / active ingredient dispersion is frozen. 3. A process for preparing a frozen stable aqueous dispersion comprising a copolymer and a water-insoluble active ingredient in a self-dispersing copolymer as defined in claim 1, wherein the active ingredient is dissolved in a minimal amount of organic solvent with vigorous stirring and excess water. was added, and frozen ^'5 to produce a fine, stable dispersion. 4. A process for preparing a frozen stable aqueous dispersion comprising a copolymer and an active ingredient, comprising dissolving a non-self-dispersing form of the copolymer as defined in claim 1 in a water-miscible organic solvent, slowly adding excess water to the solution with vigorous stirring. to the copolymer dispersion, in the case of a water-soluble active ingredient, a solution of the active ingredient in water or, in the case of a water-insoluble active substance, a solution of the active ingredient in a water miscible solvent, optionally containing water.