WO1996024331A1

WO1996024331A1 - New medical forms with prolonged effect applied in eye medicine and the method for preparation thereof

Info

Publication number: WO1996024331A1
Application number: PCT/CZ1996/000006
Authority: WO
Inventors: Miroslav Bleha; Jaroslav PRCHLÍK; Zden^¿ka SEDLÁKOVÁ; Karel Bouchal; Karel SEDLÁC^¿EK
Original assignee: Ústav Makromolekulární Chemie Akademie Ve^¿D C^¿Eské Republiky; VÚFB a.s.; Fakultní Thomayerova Nemocnice
Priority date: 1995-02-07
Filing date: 1996-02-06
Publication date: 1996-08-15
Also published as: CZ31595A3; SK105897A3; CZ285636B6

Abstract

The invention pertains to new medical forms of pharmaceutics with prolonged effect applied in eye medicine, which are formed by a pregel or gel based on the copolymers of 2-(2-carboxybenzoyloxy)ethyl methacrylate with methacrylate comonomers selected from the group comprising methyl methacrylate and butyl methacrylate, the carboxyl groups of which are at least in part modified and/or neutralized with at least one pharmaceutically active substance and/or neutralized with Na+ and/or K+ ions and/or organic bases and which contains, if it is desired, encapsulated another pharmaceutically active substances. One of the methods for the preparation of these new medical forms consists in at least partial neutralization of functional carboxyl groups of the latex, based on the copolymers of 2-(2-carboxybenzoyloxy)ethyl methacrylate with methacrylate comonomers selected from the group comprising methyl methacrylate and butyl methacrylate, with a basic pharmaceutically active substance and/or sodium hydroxide and/or potassium hydroxide and/or organic bases. The scope of the invented solution comprises also further methods for the preparation of the medical forms according to the invention.

Description

New medical forms with prolonged effect applied in eye medicine and the method for preparation thereof

Technical Field

The invention pertains to new medical forms of pharma¬ ceutics with the prolonged effect applied in ophthalmology and to the method of their preparation.

Background Art

One of the fundamental prerequisites of successful treatment is the optimal pharmacotherapeutical regime which depends, among others, on attaining the required therapeuti- cal level of medical substance in the organism and its stabilization during therapy.

For this reason and because of efforts to extent the time interval between drug administration, the medical forms with prolonged effect acquire still larger importance. These medical forms are intensively developed over the whole world, particularly in eye medicine, unfortunately, so far without completely satisfactory results.

In dosing eye drops as the most frequent medical form of ophthalmic drugs, the solution of active substance runs on the cornea and is eliminated from this area practically within 30 seconds (Nor M. Acta Ophtal. 42,727 (1964)). In the usual case of active substance passing through the cornea interface, the time of action of the active substance is insufficient for the above reason. This problem of short residence time of the administered ophthalmic drug on the eye surface is solved in part by increasing the viscosity of drops by additives based mostly on the derivatives of cellulose and poly(vinylalcohol) (Sieg J. ., Robinson J.R. , J.Phar .Sci. 66, 1222 (1977)). A considerable disadvantage of the modified forms of collyrium is, besides the difficult dosing, the deteriorated filtrabil- ity of the prepared solutions in the drops production. With respect to the necessary sterility of eye drops, the filtra¬ tion through a bacteriological filter with a small pore diameter (approx. 0.1-0.2 μ ) is prescribed in the production of this medical form. Also the application of gel plates under the eye lid is accompanied with unfavourable side effects and irritation.

The present method represents a qualitatively more efficient solution of the problem of prolonged action of the active substance on eye. It is based on the preparation of polymer materials with the affectable capacity of their transition from a dispersion form into polymeric transparent gel either "in situ" in the eye or outside the eye.

Disclosure of Invention The subject of the invention are new medical forms with prolonged effect for pharmaceutics applied in ophthalmology consisting of a pregel or gel based on the copolymers of 2-(2-carboxybenzoyloxy)ethyl methacrylate with methacrylate comonomers selected from the group comprising methyl methac- rylate and butyl methacrylate, carboxy groups of which are, at least in part, modified and/or neutralized with at least one pharmaceutically active substance and/or neutralized with Na* and/or K* ions and/or organic bases, and which pregel or gel contains, if it is desirable, another pharmaceutically active substance in an encapsulated form.

The active substances, selected from the group compris¬ ing pilocarpine, atropine, lysine base, lysine salicylate, physostigmine salicylate, sodium salt of diclofenac, timolol, carbachol, ciprofloxacine, Zn^** or their combinations, are suitable as pharmaceutically active substances according to the invention.

New medical forms according to the invention can further contain, besides the pharmaceutically active substance, also another encapsulated pharmaceutically active compound. The method for the preparation of the new medical forms according to the invention consists in, at least partial, neutralization of functional carboxy groups of a latex based on the copolymers of 2-(2-carboxybenzoyloxy)ethyl methacry¬ late with the methacrylate comonomers, selected from the group comprising methyl methacrylate and butyl methacrylate, with the basic pharmaceutically active substance and/or sodium hydroxide and/or potassium hydroxide and/or organic bases.

Another possible procedure in the preparation of the medical forms according to the invention consists in an ion-exchange reaction of the at least partially neutralized latex, based on the copolymers of 2-(2-carboxybenzoyloxy)et¬ hyl methacrylate with methacrylate comonomers selected from the group comprising methyl methacrylate and butyl methacry¬ late, with the cations of farmaceutically active substance and/or with Zn^** ions and neutralization of the residual carboxy groups.

The new medical forms according to the invention may be also prepared by the method which consists in subjecting the latex, or the at least partially neutralized latex, based on the copolymers of 2-(2-carboxybenzoyloxy)ethyl methacrylate with methacrylate comonomers selected from the group compris¬ ing methyl methacrylate and butyl methacrylate, to the reaction with at least one pharmaceutically active substance of the cationic and/or anionic character and in neutraliza¬ tion of the residual carboxy groups. The new medical forms for pharmaceutics applied in ophthalmology according to the present invention are based on our investigations which showed that the synthesized copoly- mer of 2-(2-carboxybenzoyloxy)ethyl methacrylate (CBM) with appropriately selected comonomers exhibits, in the neutral- ization of carboxyl groups with bases, a high degree of swelling and that the latex particles are transformed to gel during these changes. The transport properties of CBM materials are strongly affected by the presence of carboxyl groups, above all by the degree of neutralization which is decisive for the water content in the swelled structure of copolymers. These copolymers proved suitable polymeric carriers of ophthalmological preparations with prolonged action. The prepared emulsion types of copolymers are modified with the selected drugs during the neutralization process and then either applied in the form of dispersion, which is transformed into the gel form in eye by a small change of pH, or applied directly as a gel.

The active substances, such as pilocarpine, atropine, sodiumdiclofenac [sodium 2-(2,6-dichloroanilino)phenylaceta- te], timolol [l-(l,l-dimethylethylamino)- 3-(4-(4-morpholiny- l)-l,2,5-thiadiazol-3-yl)oxypropanol-2] , carbachol [2-N,N,N- trimethyl- ammonium ethyl urethane], ciprofloxacine [l-cyclo- -propyl-6-fluoro-1,4-dihydro-4-oxo- 7-(1-piperazinyl)-3-quin- oline carboxylic acid] , tobramycin [0-3-amino-3-deoxy-α,D-gl- uco- pyranosyl-(1,6)-O-(2,6-diamimo-2,3 ,6-trideoxy-o,D-riboh- exo-pyranosyl-l,4)-2-deoxy- D-streptamnine] or their suitable combinations, are ionically bonded to latex particles of a catex type; the remaining carboxyl groups are neutralized to Na* or K^* forms and the swelling degree of these particles in water increases in this way; in the region of pH above 6.8, a strong physical interaction between these particles occurs and, after their application on the eye cornea, the gel is formed due to the increase of pH to about 7.3 (pH of eye fluid).

The formation of gel can be also utilized for encapsula¬ tion of further types of pharmaceutics, which are not chemic- ally bonded to the functional groups of latex particles but are fixed in the gel matrix from which they are gradually released by diffusion. The combination of both ways, i.e. of the ionic bond and encapsulation, may be advantageously used for the drug types containing the pharmaceutically active components of both cationic and anionic character, e.g. Ketozolac tromethamine , where tromethamine [tris(hydroxymeth- yl)aminonethane] is ionically bonded to the latex particles and the released 5-benzoyl-2,3-dihydroxy-l,4-pyrrolizine-l carboxylic acid (Ketozolac) is encapsulated in the gel formed. Lysine salicylate may be analogously fixed in the gel; lysine is bound to the latex particles and the released salicylic acid is encapsulated in the formed gel. This gel releases the drug with retardation due to the ion-exchange reaction between the drug cations and Na⁺ of K^* present in the eye fluid or by diffusion of the encapsulated drug component from the gel. The initial latexes of copolymers of 2-(2-carboxybenzoy- loxy)- ethyl methacrylate (CBM) with the methacrylate comonomers - methyl methacrylate (MMA) , butyl methacrylate (BuMA) - contain particles of these copolymers of the size characterized by diameter d = 100-150 nm. The content of carboxyl groups in the case of CBM homopolymer attains as much as 3.6 mmol per g of latex dry substance (or 0.36 mmol per ml of 10% latex); low contents of carboxyl groups may be obtained by copolymerization of CBM with the above mentioned methacrylate comonomers. During the neutralization of COOH groups (ff^-forms) with bases, a considerable swelling of particles with water occurs depending on the neutralization degree and the volume increases about hundredtimes. If these particles contain more than 2.4 mmol COOH per g of dry substance, the formation of gel occurs at high degrees of their neutralization (Z. Sedlakovά et col., Angew.Makro ol.Chemie 201(1992) 33-48). This gel is the potentional carrier of drugs which are able to create ionic bonds with COO^' groups or which can be encapsulated in the formed gel. Bonding of drugs on the functional carboxyl groups (COOH) of the latex particles is carried out either by neutralization of the COOH groups with the basic types of pharmaceutics, e.g. ciprofloxacine, or by ion-exchange reactions of the Na⁺-forms of latex with the cations of pharmaceutics, e.g. pilocarpine or Zn^**, according to the following scheme:

-COO^" Na^* + pilocarpine.H⁺C1- >

-COO^' H⁺ pilocarpine + Na*Cl^'

An advantage of such a form of pharmaceutics application on eye cornea consists in extention the time of drug action. The prolongation of drugs is caused by diffusion course of the ion exchanging reaction

gel pilocarpine H⁺C1^"

-COOH^* -pilocarpine + Na^*Cl^' (eye fluid)

The gel slows down flooding up the pharmaceutics from the eye caused by weeping. Considerable transparency of the gel and the necessary compatibility with the eye cornea secure that the patient has not substantially worse vision during application of this medical form.

With respect to the high content of COOH groups in the latex particle (0.25-0.35 mmol per 1 ml latex), these latexes may bind as much as 70 mg drug (MW 200) in 1 ml, whereas the common medical forms are administered in concentrations 0.1-1% (10 mg per ml).

As follows from the above facts, about 20% of functional groups can be utilized for the ionic binding of drug and the remaining groups may serve for the bond of another type of drug. In the case of a single-component system, the remaining COOH groups can be transferred to the Na* form or K*form or to their combination by partial neutralization with NaOH (sodium hydroxide) or KOH (potassium hydroxide). The gels prepared in this way then contain both the desired pharmaceutics and the suitable ratio of Na^* and K^* ions which can adjust the ionic conditions in the eye.

All gels prepared from the latexes of copolymers of 2-(2-carboxybenzoyloxy)ethyl methacrylate (CBM) exhibit strong antibacterial effects and are biocompatible.

The invention is further illustrated in the examples of performance without, however, limiting the scope to them. Examples

Example 1

The latex of copolymer 2-(2-carboxybenzoyloxy)ethyl methacrylate with butyl methacrylate (CBM - BuMA) was prepared by mixing 18.6 g CBM (6.7x10* mol) and 6.3 g BuMA (4.47xl0^'2 mol) and dosing this monomer mixture into 100 ml aqueous phase; this phase contained 1 g lauryl sulfate and 0.1 g K₂S₂0₈as one of the components of redox system. Emulgat- ion of the reaction mixture required vigorous stirring (350 r.p.m.) for 15 minutes. At the same time, the reactor was inertized (flushed with nitrogen N₂). After the emulgation stage, the solution of 0.1 g sodium disulfite in 5 ml H₂0 was added and the subsequent radical emulsion copolymerization proceeded at 25°C for 24 hours. The conversion degree attained was 96%. Latex CBM - BuMA prepared in this way had the following characteristics: content of dry substance 0.2 g/ml, particle size d_n (diameter 70 nm, [COOH] = 5.37xlO^'Amol/ml. Low-molecular weight electrolytes (residues of the initiation system and the reaction products of initiation reaction) were removed by pressure filtration of the latex with deionization water through the membrane DIAFLOW XM 300 (product of AMICON, USA) ; the process was checked by measuring conductivity of the filtrate and stopped when conductivity lambda = 600 μS was attained. The latex processed in the described way was partially neutralized with 0.1 M solution of lysine base and then with 0.5 M NaOH (sodium hydroxide) until a pregel state was achieved. The procedure consisted in the stepwise neutralization of 10 ml processed latex CBM - BuMA with 27 ml 0.1 M lysine base, which corresponds to 50% conversion of COOH functional groups of the latex to lysine monophth late. The gradual addition of 4.5 ml 0.5 M NaOH ionized further COOH groups (the content of COO^' groups corresponded to about 90% conversion of COOH groups) forming the pregel with particle size d_n = 500-700 nm. The pregel contained 10 mg lysine/ml (1 wt.%). β

Example 2

The latex of CBM - BuMA copolymer prepared according to Example 1 with the distinction that the aqeous phase con¬ tained 0.5 g lauryl sulfate/100 ml H₂0, contained 0.2 g dry copolymer/ml, had particle size d„ = 100 nm and [COOH] = 5.3x10^'* ol/ml. After purification by pressure filtration, 10 ml of this latex was neutralized with 2.7 ml 0.1 M lysine base (2.7xl0⁴mol) and further neutralization of COOH groups was carried out with a mixture of 0.25 M NaOH (sodium hydroxide) and 0.25 M KOH (potassium hydroxide) in such a way, that about 90% total COOH groups was neutralized and the latex formed a pregel of pH about 6.8-6.9. This modified pregel contained 0.2 wt.% lysine (2 mg/ l) and the ratio Na^*/K^* (of sodium to potassium ions) corresponded to about 1.

Example 3

The latex of copolymer CBM - BuMA, prepared according to Example 2, was pressure filtered, mixed with lysine salicy¬ late and then transformed to a pregel, which contained encapsulated lysine salicylate, by neutralization of func¬ tional groups with 0.5 M NaOH. The procedure consisted in stirring 10 ml latex with 700 mg lysine salicylate in 8 ml H₂0 for 48 hours. The gradual addition of 8.5 ml 0.5 M NaOH gave rise to the pregel containing 3 wt.% lysine salicylate (30 mg lysine salicylate/ml) .

Example 4

The latex of copolymer CBM - BuMA, prepared according to Example 1 with the distinction that the aqeous phase con- tained 0.25 g lauryl sulfate, and characterized by parame¬ ters: content of dry substance 0.18 g/ml, ά-, = 150 n , [COOH] = 5.25X10^"4 mol cm^'3, was refined and then modified with Zn^** ions by the following procedure: 10 ml latex was stirred with 20 mg Zn(CH₃COO)₂. 2 H₂0 (zinc acetate) dissolved in 5 ml H₂0 ([Zn**] = 0.9x10^' mol Zn) at 25°C for 2 hours and then the residual COOH groups were neutralized with 0.5 M NaOH until the pregel was formed (neutralization degree about 85%, pH 6.7 to 6.8); the pregel contained approx. 0.27 wt.% Zn** = 2.7 mg Zn^**/ml.

Example 5 The latex CBM - BuMA modified with Zn^** ions according to Example 4 was neutralized, after the reaction with the aqueous solution containing 20 mg Zn(CH₃COO)₂, first with 0.1 M solution of lysine base (10 ml) and then with approx. 4 ml of the mixture of 0.25 M NaOH and 0.25 M KOH to the degree of neutralization of COOH groups about 90% when the latex created the pregel state with particle size d„ = 600-800 nm; pH 6.8. The pregel contained 0.46 wt.% lysine (4.6 mg/ml) and 0.17 wt.% Zn^** (1.7 mg/ml); the Na^*/K* ratio was about 1.

Example 6

The latex CBM - BuMA prepared according to Example 4 was mixed with lysine salicylate and then neutralized to create the pregel containing encapsulated lysine salicylate and ionically bonded Zn^** ions. The procedure consisted in mixing 10 ml latex with 20 mg Zn(CH₃COO)₂.2 H₂0 dissolved in 5 ml H₂0 [Zn^**= 0.9x 10^"4mol] at 25°C for 2 hours, followed by addition of 700 mg lysine salicylate dissolved in 8 ml H₂0. The mixture was then stirred for 24 hours at 25°C and then the pregel was created by neutralization with 0.5 M NaOH, which contained 23 mg/ml (2.3 wt.%) of encapsulated lysine salicylate and 2.3 mg Zn^**/ml (0.23 wt.%).

Example 7

The latex CBM - BuMA prepared according to Example 1 was pressure filtered and then partially neutralized (about 10% COOH groups) with 0.5 M NaOH and subjected to the ion-exchan¬ ging reaction with physostigminium salicylate. The following neutralization with 0.5 M NaOH created the pregel containing ionically bonded physostigminium cation and encapsulated sodium salicylate. The procedure consisted in mixing 10 ml latex with 60 mg physostigminium salicylate in 6 ml H₂0 for 24 hours at 25°C and the following neutralization with 0.5 M NaOH (about 9 ml) which created the pregel containing physostigminium cations in the amount corresponding to 2.4 mg physostigminium salicylate per ml (0.24 wt.%).

Example 8

The latex CBM - BuMA prepared according to Example 1 was pressure filtered, partially neutralized with 0.5 M NaOH (about 10% COOH groups), and then modified with Zn*^* ions and physostigminium salicylate. The following neutralization of remaining COOH groups with 0.5 M NaOH converted the latex into the pregel containing Zn^** and the ionically bonded physostigminium cation. For example, 10 ml latex was neutral¬ ized with 1 ml 0.5 M NaOH, 20 mg Zn(CH₃COO)₂.2 H₂0 in 5 ml H₂0 was added and the mixture was stirred for 2 hours at 25°C. The solution containing 60 mg physostigminium salicylate in 6 ml H₂0 was then dropwise added and stirring was continued for further 24 hours. The following neutralization with 0.5 M NaOH (about 8 ml) formed the pregel containing 2 mg physosti¬ gminium cation/ml (0.2 wt.%) and 2 mg Zn**/ml (0.2 wt.%).

Example 9

The latexes CBM - BuMA prepared according to Example 2 may be partially neutralized after pressure filtration with 1-(1,l-dimethylethylamino)-3-(4-(4-morpholinyl)-1,2,5-thia- diazol-3-yl)oxypropanol-2 (Timolol) and then another part of the latex functional COOH groups can be neutralized with 0.5 M NaOH. In the subsequent ion-exchanging reaction, N-(2-(ami- nocarbonyl)oxy)ethyl-N,N,N-trimethylammonium cation (Carba- chol) may be ionically bonded on latex particles and may form the gel containing the combination of both pharmaceutics by addition further portion of 0.5 M NaOH at pH 6.8. The following procedure was used: 10 ml latex was partly neutral¬ ized with 31.6 mg Timolol (10* mol - 0.34 wt.%), 5 ml 0.5M NaOH was added, the latex was mixed with 90 mg Carbachol (5x10^"4mol - 0.9 wt.%) and, after 3 hours of stirring at 25°C, pH was adjusted to 6.8 by addition of 0.5 M NaOH to create the pregel from latex particles. Example 10

The latex CBM - BuMA prepared according to Example 1 was pressure filtered, modified with l-cyclopropyl-6-fluoro- -1,4-dihydro-4-oxo-7-(1-piperazinyl)-3- quinolinecarboxylic acid (Ciprofloxacine) and the pregel containing Ciprofloxaci- ne was formed by the following neutralization with 0.5 M NaOH up to the pH value of 6.8. The procedure consisted in mixing 10 ml latex with 33 mg antibiotics for 3 hours at 20°C followed by neutralization with 9 ml 0.5 M NaOH under vigorous stirring. Temperature 20°C was kept by cooling and the pregel with pH 6.8 was formed after metering the NaOH solution.

Example 11 The latex CBM - BuMA prepared according to Example 4 was modified with Zn^** ions and then mixed with an aqueous solution of sodium (2-(2,6-dichloroanilino)phenyl)acetate (sodium Diclophenac) . The following neutralization with 0.5 M NaOH (KOH or KOH-NaOH mixture) created the pregel which contained ionically bonded Zn^** cations and encapsulated sodium Diclophenac. The following procedure was used: 10 ml latex was mixed with 20 mg Zn(CH₃COO)₂.2 H₂0 dissolved in 8 ml H₂0 at 25°C for 2 hours, then the solution of 30 mg Na* Diclophenac in 5 ml H0 was dropwise added into the latex and the subsequent neutralization with 0.5 M NaOH created the pregel which contained 2.3 mg Zn^**/ml and about 1 mg Dicloph- enac/ml.

Claims

1. New medical forms of pharmaceutics with a prolonged effect, applied in eye medicine, formed by a pregel or gel based on the copolymers of 2-(2-carboxybenzoyloxy)e- thyl methacrylate with methacrylate comonomers selected from the group comprising methyl methacrylate and butyl methacrylate, carboxyl groups of which are at least in part modified and/or neutralized by at least one pharma- ceutically active substance and/or neutralized with Na* and/or K* ions and/or organic bases and which, if it is desired, contains encapsulated another pharmaceutically active substance.

2. New medical forms of pharmaceutics with a prolonged effect, applied in eye medicine, according to Claim 1, wherein the substances selected from the group compris¬ ing pilocarpine, atropine, lysine base, lysine salicy¬ late, physostigminium salicylate, sodium diclophenac, timolol, carbachol, ciprofloxacine, Zn^** ions or their combinations are used as the pharmaceutically active substances.

3. The new medical forms for pharmaceutics applied in eye medicine according to Claims 1 and 2, wherein the said forms contain encapsulated pharmaceutically active substance.

4. The method for preparation the new medical forms accord- ing to Claims 1 to 3, wherein functional carboxyl groups of the latex based on copolymers of 2-(2-carboxybenzoyl- oxy)ethyl methacrylate with methacrylate comonomers selected from the group comprising methyl methacrylate and butyl methacrylate are neutralized, at least in part, with a basic pharmaceutically active substance and/or sodium hydroxide and/or potassium hydroxide and/or organic bases.

5. The method for preparation the new medical forms accord¬ ing to Claims 1 to 3, wherein the at least partially neutralized latex, based on the copolymers of 2-(2-carb- oxybenzoyloxy)-ethyl methacrylate with methacrylate comonomers selected from the group comprising methyl methacrylate and butyl methacrylate, is subjected to the ion-exchanging reaction with cations of the pharmaceuti¬ cally active substance and/or Zn^** ions and the remaining carboxylic groups are neutralized.

6. The method for preparation new medical forms according to Claims 1 to 3, wherein the latex and/or at least partially neutralized latex, based on the copolymers of 2-(2-carboxybenzoyloxy)ethylmethacrylatewithmethacry- late comonomers selected from the group comprising methyl methacrylate and butyl methacrylate, is subjected to the reaction with at least one pharmaceutically active substance of the cationic and/or anionic charac¬ ter and the remaining carboxyl groups are neutralized.