CS252559B1 - Polymer stabilizer of emulsion type water in oil - Google Patents

Abstract

A polymeric stabilizer of emulsions of an aqueous phase in a phase of water-immiscible liquid, especially for the preparation of microparticles, consists of poly ( alpha -amino acid) derivatives based on monomer units of the general formula <IMAGE> where n = 1 to 4, X is oxygen or a -NH- group, and R is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl or polyhydroxyalkyl, a radical derived from alkanoic or hydroxyalkanoic acid, where the alkyl has a linear, cyclic or branched aliphatic chain with 1 to 18 carbon atoms, or arylalkyl, wherein the copolymer may contain monomer units of various above described types in its chain. The preparations of spherical microparticles of starch, dextran or human serum albumine using the above stabilizer are described.

Description

Author of the invention

RYPÁČEK FRANTIŠEK RNNo. CSc, DROBNIK JAROSLAV doc. RNDr. CSc., SAUDEK VLADIMIR RNDr. CSc., PRAGUE (54) Polymer stabilizer of the water-in-oil emulsion

The invention relates to a polymeric stabilizer of water-phase emulsions in the water-immiscible cappain phase, especially in the preparation of micro-particles.

The object of the invention is a polymer stabilizer of the water-in-oil emulsion characterized by a thorn that consists of poly (a-a-amino acid) derivatives based on the mono-mineral units of the formula -NH-CH-CO-I.

(ch ₂ ) _n

I ^{2 n} CO-XR where η = 1 to 2, X is oxygen or -NH- and R is hydrogen, alkyl, hydroxyaacyl, wherein the alkyl may be a linear, cyclic or branched aliphatic chain of 1 to 18 carbon atoms, or arylalkyl, wherein the copolymer may contain in the chain a unit of different types.

The present invention relates to a polymeric stabilizer of water-phase emulsions in a water-immiscible liquid phase, in particular in the preparation of micro-fluids.

Suspensions of sweet spherical particles represent a very promising form of drug delivery in pharmaceuticals or find use in diagnosis. This form combines the advantages of solid implantation forms for controlled dosing of drug substances with the advantages of a solution form - i.e., an easy way of dosing, administration by injection, affecting distraction in the body, controlled blood circulation and the like .

Spherical waterborne or water-soluble polymers are generally prepared in a dispersion system under conditions where the aqueous solution of the condensed polymer or monomer is dispersed in a continuous phase in the form of a water-in-oil emulsion and is appropriately tapped during the preparation by bilutic sulfurization. The dispersion of the dispersed aqueous phase in the form of spherical particles.

The difficulty in this preparation is the stabilization of the dispersion, especially in the pre-gel stage, when the viscosity of the particles increases sharply, the particles become sticky and tend to aggregate. The aggregation of the particles is prevented by both intensive stirring of the dispersion, thereby separating the particles by shear, and by providing a suitable stabilizer, i.e. a surfactant, which stabilizes the interface between the aqueous and organic phases. The stabilizing efficiency of the surfactants increases with the molecular weight and the most effective stabilizers are the polymers containing the hydrophilic and hydrophobic moieties of the molecule. The command is polyvinyl acetate.

Particles prepared for medical purposes, especially those intended for parenteral ingestion in human exchange, must comply with the toxicological requirements for the safety and biological safety of the substances and milling agents used. For a possible stabilizer, these requirements imply that either the colony must be removable from the resulting mortar, which is all the more difficult the more effective it is to stabilize, or be a non-toxic, inert, eventually capable of being isolated and eliminated from the body. In the case of a polymeric stabilizer, this requirement is difficult to meet for non-biodegradable polymers.

We have now found that an effective polymeric emulsion in the preparation of water-in-oil microspheres are polymers and copolymers characterized in that they are derivatives of aols (IIIa-azitokyseeite) on the basis of units of the general formula

-NH-CH-COI

AND

CO-XR where η = 1 to 2, X is O or -NH- and R is hydrogen, alkyl, hydrooyl, wherein the alkyl may be a linear, cyclic or branched chain of 1 to 18 carbon atoms, or irylilkyl, the copolymer may contain оопошогп in the chain! units of different types.

Staliliiáeoo is further characterized in that mmOekulová weight pouHtých polymers and ^ οΙ ^ οθ ^ ^MU E be between 10 ^{3 and} 10 ^{6 EXAMPLE EN} eo ^r stibilňič ^ ^Prior ine ^to at ^Yss s u ^ o ^ Me ^ with higher mececular manure. '

An advantage of the stabilizer according to the invention is that the hydrophobic portion of the acokyoeric stabilizer is composed of a major part of the polymeric moiety, with its azoalbenzoate and hence the affinity for the continental phase controlled by the aloxybicolithol alkyl, tapped by the number of carbon atoms of the iliphite. As the fatty moiety of the polymeric stabilizer according to the invention, it may be either the terminal carboxyl groups formed by hydrolysis of the alkyl ester linkages or the alcoholic groups introduced by iminolysis of the amino alcohol, tapaic and iminoethalium.

A particularly advantageous feature of the inventive azo-ionic stabilizer is that the stabilizing effect may increase during the course of the reaction by increasing the polarity of the hydrophilic portion of the chain in contact with the aqueous phase due to the hydrolysis of other alkyl esters and the formation of new polar groups. a tendency to aggregate aqueous phase particles, for example due to viscosity increase.

A particularly advantageous consequence of the high efficiency is the possibility of proceeding according to the invention such that after the initial dispersion of the dispersion it is possible to reduce the mixing intensity or stirring completely and the reaction can be completed until the particles are recombined. A particularly important advantage of polymers of the poly (grm-alkyl-L-guramans) type and of the emulsion stabilizers used as emulsion stabilizers is that these polymers can be degraded in the body to non-toxic products which are either metabolizable or eliminable from the body.

The degradation of the polymer by enzymes cleaving the peppidic linkages can occur either after polymer hydrolysis, for example by hydrolysis of the alkyl ester linkages after particle soliriation, or directly in the body after cleavage of the alkyl groups by esterase enzymes or by direct hydrolysis.

The degradation of the stabilizer of the process is that it does not matter if part of the stabilizer is incorporated into the microspheres so that they are not removed during preparation, since these residues are degraded in the body and have no toxicological significance. This renders the stabilizer of the invention particularly suitable for the preparation of completely bisdegrable particles for parenneral ingestion in the homeworm meedcin.

The starburst of the invention is exemplified by, but not limited to, the following examples.

Example 1 mg of poly (L-grInarbeeízУ glutrmátu) (PBG) (M _w = 110,000) was dissolved in 8 ml of ^{1,2-ddchllr-Star} mandrel within a cylindrical reaction to ^{D Both of} the ^p at en ^{é h} and MIC ^d hem and tempered to ⁵⁰ ° C. 2 ml of an aqueous solution containing 0.8 g of dextran T-40 (Pharmmaia, Uppsala) and 0.2 g of sodium hydroxide (NaOH) were added. The stirrer speed was set to 750 rpm, thereby dispersing the aqueous phase to particles with a diameter of about 60 µm. 0.39 ml (5 ml) of freshly distilled piperidine was added. The reaction was allowed to proceed for 8 hours with constant stirring. The average particle size at the end of the reaction was 52 and 18 µm, respectively. The particles were separated R-tubs, washed with 5 x 50 ml of dioxane and 50 suspended in 1 liter 0.5 ml ^"1 sodium hydroxide (NaOH). After 6 h at Stony temporary ^ o ^ ^ i would shake] and a suspension of ^d ^ .Ю юг ^ ^ пг and washed with water. The gelled particles obtained are spherical, hydrophilic, separated without a tendency to aggregate. Yield 0.65 g of dry homogeneous particles.

EXAMPLE 2 mg of poly (grmrbeeize-L-gluraeSS) (PBG) (M + = 110,000) was dissolved in 8 ml of 1,2-dichloro-Sr. 2.6 ml of an aqueous solution containing 1.2 g of soluble starch (Lachema) and 0.2 g of sodium hydroxide (NaOH) were added. Stirrer speed set so that the particles are about ⁶⁰ microns in ^{the P} r ^of mers, and the flicker ²⁰ min ^p s ^p te Lot ⁴⁰ ° C. Added ^0.31 ml ⁽⁴ MNO - -pii LLR ^hyr cephalosporin ^h and stirred for another 5 minutes. Then, stirring was stopped and the reaction mixture (dispersion), allowed to stand at te ^p Lot ⁴⁰ ° C ^{for 18 h. EXAMPLE specific one} v ^ _]> ^ ⁱ ^ ^{to the} axis ^{t of} particle ^ ^f ^ sperejov dam on ^{the p} Ocato in the reaction was 62 T 22 / n the end of the reaction was 56 ± 28 .mu.m. the resulting spherical particles were washed with 50 ml of 1,2-riihllr-trnž, 3.times.50 ml of 1,4-dioxane and further processed as in Example 1. 0.8 g of dry potash were obtained.

Example 3 mg of poly (Grma-meeyl '^ L glutamSnu) _(Mw - 3,000,000) and 0.2 ml diihloroitové kyseainy ponecMno 20 ^hour s ^ e ^ ^p lo ^{of 60} ° C. ^P s ^be well ^7.65 ml ^{1, 2} - ^(hl or RII-Tanzi and ^0.35 mL ^ri-r amiíž and the resulting solution of ^p tepilo s ^ 60 ° C. The temperature lowered to ⁴⁰ ° C and p ^r i ^gives no -6 ml in n ^{d eh} solution of

252559 4 containing 1.2 g of soluble starch (Lachema) and 0.2 g of sodium hydroxide (NaOH). The stirrer speed was set at 750 rpm and a 16 and 8 µm particle size dispersion was obtained. 0.4 ml (5 CuCl) epicdoto-ri-nu ^ rea and the mixture ponecMna without míclrání at ^pl te ^rt-40 ° C ^{for 18 h.} Obtained spherical gel particles with an average diameter of 18-12 µm. The particles were sedimented by centrifugation, washed 3x with 50 ml dioxane, suspended in 50 ml 0.3 mol 1 ^L phosphate buffer pH 8.0. After standing at room temperature for 20 h, the particles were washed with water. The particles obtained are spherical in shape, hydrophilic, non-aggressive in an aqueous medium. Yield 0.75 g of dry hmootinosi particles.

Example 4 mg of poly (ghcc-beenyd-L-gluhacate) (PBG) dissolved in 30 ml of 1,2-difluoroth. Adding a solution of 1 g lddského serum albumin in 5 ml of 0.1 ¹ of phosphate bond COKI pH 7.6 and mixing the dispersion for ^ Voren pushes a particle size of ^{No. 40 y} m. The reaction to ^D temperovna both at ⁴ ° C and ^BC IDL ^and no 0 ² ml utaraMeh ^ ^ u. After 2 hours of ^reaction at ⁴ ° C s pridetoo ^0, 2 ml of 2-hcinoethnolu and retain ^and no further ^{up 1} s ⁴ ° C. Sus ^p Enzo částoc washed with ³ x ¹⁵⁰ mL niomtanu ^ is ^ J ^ TCE nkrát dicUloeehanec cold acetone (1: 1) and converted to water, with water and 0.1% alpha- (4-okkylfenyltopolycxiran (Triton X -100) and suspended in 0.1 M phosphate bond pH 8.0 After 20 U standing at 4 ° C non-agglutinating albumin cicrtspherd was obtained.

EXAMPLE 5 mg Pold (bnth bnnzyl-L-hsphoStu) M _w = 60,000) were prepared for the procedure used in PBG příkaadu 1. The resulting gel particles were Uydrolilní spherical shape with no tendency to aggregation. The yield was 0.65 g of dry particulate matter.

Claims (1)

SUBJECT OF THE INVENTION Polymer stabilizer of the water-in-oil emulsion, characterized in that it consists of polyd derivatives (haloacintkysenin) based on monomer units of the general formula -NH-CH-CO 1 < ^{CH 2} > _n CO-XR wherein n »1 to 2, X is oxygen or -NH- and R is hydrogen, alkyl, hydroxy, and alkyl wherein the alkyl may be a linear, cyclic or branched aliphatic chain of 1 to 18 carbon atoms, or arylalkyl přčeemž copolymer may contain in the chain units of different mononmení ^ypu then t ^ and ^ e ^ kojDol MMA! deculp density in the range 10 ^{3 to 10 10} . Seveгtgohfih, n. P., MOST Price 2,40 Kčs