CN1687159A - Combination of acrylic ester containing ester group including partial alkoxyl - Google Patents

Abstract

The present invention relates to a kind of composition containing the acrylic acid ester of alkoxy group of ester moiety, and this composition comprises: (A) a kind of acrylate moiety has alkoxy group; (B) a kind of acrylate or Acrylamide monomer; (C) a photoinitiator, accounting for 0.1% to 15% of the mass of the composition; the ratio of monomers A and B in the composition can be adjusted arbitrarily. The polymer film prepared from this composition can be used as a controlled-release film in transdermal drug delivery system TDDs. By adjusting the type and content of monomers A and B in the composition, the physical and chemical properties of the film can be fine-tuned, and the rapid preparation is suitable for Controlled Release Membranes in Transdermal Delivery Systems for Different Drugs.

Description

Compositions comprising acrylates with alkoxy groups in the ester moiety

technical field

The invention relates to a photocurable monomer composition, in particular to a composition containing an acrylate with an alkoxy group in the ester group, which can be used to prepare a controlled-release film in a transdermal drug delivery system.

Background technique

The transdermal drug delivery system refers to the controlled release dosage form in which the drug is released from a specially designed device, absorbed through the intact skin, and enters the systemic blood system. Transdermal drug delivery systems can basically be divided into two categories, namely membrane-controlled release type and matrix diffusion type. Membrane-controlled transdermal drug delivery system is a drug or transdermal absorption enhancer wrapped by a controlled-release film or other controlled-release material to form a reservoir, and the release rate of the drug is controlled by the properties of the controlled-release film or controlled-release material. Hyoscyamine (trade name Transderm-Scop) and clonidine (trade name CatapresTTS) in the currently commercially available patches are membrane-controlled, and the control membrane is a microporous polypropylene membrane; nitroglycerin (trade name Transderm-Nitro), fentanyl (trade name Duragesic), estradiol (trade name Estraderm), testosterone (trade name Androderm) are film-controlled, and the controlled-release film is polyethylene-vinyl acetate; Nicotine (trade name NicoDerm CQ) is film-controlled, The control film is a polyethylene film.

The use of microporous membranes to control drug release rates is described in European Patent No. 46069, US Patent No. 3,797,494. The pores of the membrane are from 0.1 to 0.85, the curvature of the membrane is from 1 to 10, and the thickness of the membrane is from 10 to 100 microns. Examples of membranes are polypropylene, polytetrafluoroethylene, polycarbonate, polyvinyl chloride, cellulose acetate, nitric acid Cellulose, polyacrylonitrile, etc. Their disadvantage is that there are few types of microporous membranes available for selection, which cannot satisfy more medicines to be made into transdermal dosage forms.

In the scopolamine patch described in US Patent No. 6,537,571B1 and the nitroglycerin patch described in US Patent No. 4,681,584, the release-controlling membranes used are all ethylene-vinyl acetate copolymers. The disadvantage is the residual problem of organic solvent in ethylene-vinyl acetate copolymer, and the need to constantly adjust the content of vinyl acetate to adjust the permeability of the drug.

In the clonidine patch described in European Patent No. 1103260A2 and U.S. Patent No. 2004/0028726A1, using -(2-ethyl)hexyl acrylate, methyl methacrylate, acrylic acid and vinyl acetate, free Based on the polymerization reaction, the obtained copolymer is used as the pressure-sensitive adhesive layer and reservoir layer in the patch, and can control the release of drugs at the same time. The disadvantage is that the free radical polymerization reaction is affected by many factors, such as reaction time, reaction temperature, initial concentration of raw materials, solvents and other factors, and the patch also has the problem of residual organic solvents.

The films used in the transdermal drug delivery system generally lack the types of controlled release films, and the selectivity is small, which brings great obstacles to the development of transdermal drug delivery preparations.

Contents of the invention

The purpose of the present invention is to provide a polymer monomer composition with excellent curing performance and capable of producing a controlled-release membrane used in transdermal drug delivery systems against the deficiencies of the prior art.

In order to solve the shortcomings of the lack of types of controlled-release membranes in the existing transdermal drug delivery system, the present invention found on the basis of extensive and in-depth research that a variety of types can be obtained by using a special photocurable monomer composition. Controlled release membrane with excellent performance. The composition comprises: (A) an acrylic ester having an alkoxy group in the ester group; (B) an acrylic ester or acrylamide monomer; (C) a photoinitiator, accounting for 0.1% of the mass of the composition ~15%; the ratio of monomers A and B in the composition can be adjusted arbitrarily.

The monomers with alkoxy groups in the ester groups used in the present invention are represented by the general formula CR ₂ R ₁ =CR ₃ COOR ₄ , wherein R ₁ , R ₂ , and R ₃ are any substituents, including -H, - CH ₃ , -C ₆ H ₅ , -CH=CH ₂ , -OH, -COOH, -OCH ₃ , -SO ₃ H, -NH ₂ , -N(CH ₃ ) ₃ Cl, R ₄ is an alkoxy Substituents for radicals, including -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -(CH ₂ ) ₃ OCH ₃ , -(CH ₂ ) ₄ OCH ₃ , -(CH ₂ ) ₅ OCH ₃ , -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ OC ₂ H ₅ , -CH ₂ CH ₂ OC ₃ H ₇ , -CH ₂ CH ₂ OCH ₂ OC ₆ H ₅ , -C ₂ H ₄ CH ₂ OCH ₃ , -C _{2H4CH2OC2H5 , -C3H6CH2OCH3 , -C3H6CH2OC2H5 , -C3H6CH2OC6H5 . _ _ _ _ _ _ _ _ _ _ _} The monomer used in the present invention is 2-butoxyethyl acrylate, but it is not limited to this monomer, and all acrylates containing alkoxy groups in the ester group can be used as potential substitutes for this monomer. Examples can be listed as follows: 2-methoxyethyl (meth)acrylate, 2-ethoxyethyl (meth)acrylate, 2-propoxyethyl (meth)acrylate, (methyl) ) acrylate-3-methoxypropyl, (meth)acrylate-3-ethoxypropyl, (meth)acrylate-3-propoxypropyl, (meth)acrylate-3-butoxy Propyl ester, 2-methoxypropyl (meth)acrylate, 2-ethoxypropyl (meth)acrylate, 2-propoxypropyl (meth)acrylate, (meth)acrylic acid -2-butoxypropyl, (meth)acrylate-2-phenoxyethyl, (meth)acrylate-2-phenoxypropyl, (meth)acrylate-3-phenoxypropyl , (meth)acrylate-2-phenoxybutyl, (meth)acrylate-3-phenoxybutyl, (meth)acrylate-4-phenoxybutyl, etc., but not limited to the above monomers listed.

The acrylate monomer used in the present invention can be represented by the general formula CR ₂ R ₁ =CR ₃ COOR ₄ , where R ₁ , R ₂ , and R ₃ can be any substituents, such as -H, -CH ₃ , - C ₆ H ₅ , -CH=CH ₂ , -OH, -COOH, -OCH ₃ , -SO ₃ H, -NH ₂ , -N(CH ₃ ) ₃ Cl, etc., but not limited to the substituents listed above . The R ₄ substituent can be an alkoxy group, and the example is the same as the acrylate monomer with an alkoxy group in the ester group.

The _R substituting group in the general formula of the acrylate monomer can also be an alkane group, and the example used in the present invention is n-dodecyl acrylate, but it is not limited to this monomer, and all _R Substituting groups are Alkane-based acrylates are all potential replacements for this monomer. Examples are as follows: -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -(CH ₂ ) ₃ CH ₃ , -(CH ₂ ) ₄ CH ₃ , -(CH ₂ ) ₅ CH ₃ , -(CH ₂ ) ₇ CH ₃ , -(CH ₂ ) ₁₁ CH ₃ , -CH ₂ CH═CH ₂ , etc., but not limited to the substituents listed above.

The _R substituent in the general formula of the acrylate monomer can be a group substituted by an ester group, and the example used in the present invention is 1,6-hexanediol dimethacrylate, but not limited to this Monomer, acrylates in which all R ₄ substituents are ester substituted groups are potential replacements for this monomer. Examples are as follows: -CH ₂ OOCCH=CH ₂ , -(CH ₂ ) ₂ OOCCH=CH ₂ , -(CH ₂ ) ₃ OOCCH=CH ₂ , -(CH ₂ ) ₄ OOCCH=CH ₂ , -(CH ₂ ) ₅ OOCCH=CH ₂ , -(CH ₂ ) ₆ OOCCH=CH ₂ , -(CH ₂ ) ₈ OOCCH=CH ₂ , -(CH ₂ ) ₂ OOCC(CH ₃ )=CH ₂ , -(CH ₂ ) ₃ OOCC( CH ₃ )=CH ₂ , -(CH ₂ ) ₄ OOCC(CH ₃ )=CH ₂ , -(CH ₂ ) ₅ OOCC(CH ₃ )=CH ₂ , -(CH ₂ ) ₆ OOCC(CH ₃ )=CH _2. -(CH ₂ ) ₈ OOCC(CH ₃ )=CH ₂ and the like, but not limited to the substituents listed above.

The _R substituent in the general formula of the acrylate monomer can be a hydroxyl-substituted group, and the example used in the present invention is 2-hydroxyl-3-phenoxypropyl acrylate, but not limited to this single acrylates in which all R ₄ substituents are hydroxy-substituted groups can be used as potential replacements for these two monomers. Examples are as follows: -CH ₂ OH, -(CH ₂ ) ₂ OH, -(CH ₂ ) ₃ OH, -(CH ₂ ) ₄ OH, -(CH ₂ ) ₅ OH, -CH ₂ CH(OH)CH ₃ , -CH ₂ CH(OH)C ₂ H ₅ , -CH ₂ CH(OH)C ₃ H ₇ , -CH ₂ CH(OH)CH ₂ OC ₆ H ₅ , -C ₂ H ₅ CH(OH)CH ₃ , -C ₂ H ₅ CH(OH)C ₂ H ₅ , -C ₃ H ₆ CH(OH)CH ₃ , -C ₃ H ₆ CH(OH)C ₂ H ₅ , -C ₃ H ₆ (OH)CH ₂ OC ₆ H ₅ and the like, but not limited to the substituents listed above.

The R substituting group in the general formula of the acrylate monomer can be a group substituted by a carboxyl group. _The example used in the present invention is 2-carboxyethyl acrylate, but it is not limited to this monomer, and all _R substituting Acrylates in which the group is a carboxyl-substituted group are potential replacements for this monomer. Examples are as follows: -CH ₂ COOH, -(CH ₂ ) ₂ COOH, -(CH ₂ ) ₃ COOH, -(CH ₂ ) ₄ COOH, -(CH ₂ ) ₅ COOH, -(CH ₂ ) ₆ COOH, -( CH ₂ ) ₈ COOH, -(CH ₂ ) ₁₂ COOH, etc., but not limited to the substituents listed above.

The acrylamide monomer of the present invention can be represented by the general formula CR ₂ R ₁ =CR ₃ CONR ₄ , wherein the definitions of R ₁ , R ₂ , R ₃ and R ₄ are the same as those of the acrylate monomer. The acrylamide monomer used in the present invention is N-(1,1-dimethyl-3-oxobutyl)-acrylamide, but it is not limited to this monomer, all acrylamide monomers can as a potential replacement for this monomer. Examples of acrylamide monomers are as follows: (meth)acrylamide, N,N-dimethyl (meth)acrylamide, N-isopropyl (meth)acrylamide, N-(butoxymethyl) )(meth)acrylamide, N-(methylol)(meth)acrylamide, N-[(trimethylol)methyl](meth)acrylamide, N-[3-(dimethyl) amino)propyl](meth)acrylamide and the like, but not limited to the monomers listed above.

Photoinitiators that can be used in the present invention include all initiators for UV curing, such as benzophenone peroxide, 1-hydroxycyclohexyl phenyl ketone, benzoin propyl ether, but not limited to these Photoinitiators, all photoinitiators that are sensitive to ultraviolet light and can initiate the curing reaction of monomers are not limited.

The polymer film prepared by the composition of the present invention can be used as a controlled-release film in transdermal drug delivery system (TDDs), by adjusting the type and content of monomers A and B in the composition, the physical and chemical properties of the film can be fine-tuned, Rapid preparation of controlled-release membranes for transdermal drug delivery systems for different drugs. When using the composition of the present invention to prepare a controlled-release film, plasticizers, including citrate, phthalate, sebacate, etc., can be added to the mixed solution to further improve the physical properties of the controlled-release film. The invention broadens the types of materials for preparing the controlled-release membrane in the transdermal drug delivery system, and expands the range of material selection.

Description of drawings

Fig. 1 is the permeability test of the cured film obtained by UV curing after mixing 2-butoxy ethyl acrylate and n-dodecyl acrylate in a mass ratio of 2:8 and taking 30ul.

Fig. 2 is 2-butoxyethyl acrylate and 4-hydroxybutyl acrylate mixed at a mass ratio of 2: 8 and then take 30ul, the permeability test of the cured film obtained by UV curing and the in vitro transdermal test of animal skin Comparison.

Fig. 3 is 2-butoxyethyl acrylate and N-(1,1-dimethyl-3-oxobutyl)-acrylamide mixed according to mass according to the mass ratio of 2:8, take 30ul, and obtain by UV curing Permeability experiments of cured membranes.

Detailed ways

The following examples of implementation of the present invention are presented for the purpose of illustration, but not to limit the present invention.

Example 1

Mix 2-butoxyethyl acrylate and n-dodecyl acrylate in a mass ratio of 2:8, then add 5% (w/w) benzophenone peroxide, dissolve, filter, and take the mixed solution 30ul, put it on the carrier base, spread it flat, and place it in a UV curing instrument to cure completely.

The obtained cured film was placed in a modified Franz diffusion cell, the supply cell was a methyl salicylate solution, and the receiver cell was a pH 7.4 phosphate buffer. The release rate of methyl salicylate was analyzed by high performance liquid chromatography. See Figure 1: the permeability test of methyl salicylate on the cured film (correlation coefficient r=0.9873), it can be seen from the figure that the cured film has a linear controlled release effect on the drug.

Example 2

Mix 2-butoxyethyl acrylate and 4-hydroxybutyl acrylate in a mass ratio of 2:8, then add 5% (w/w) benzophenone peroxide, dissolve, filter, and take 30ul of the mixed solution , put it on the carrier substrate, spread it flat, and place it in a UV curing device to cure completely.

The obtained cured film was placed in a modified Franz diffusion cell, the supply cell was a 1 mg/ml clonidine hydrochloride aqueous solution, and the receiver cell was a phosphate buffer solution with a pH of 7.4. The release rate of clonidine hydrochloride was analyzed by high performance liquid chromatography.

For animal skin comparison, fresh abdominal skin of Kunming mice was placed in a modified Franz diffusion cell, the supply cell was 1mg/ml clonidine hydrochloride aqueous solution, and the receiver cell was phosphate buffer saline at pH 7.4. The release rate of clonidine hydrochloride was analyzed by high performance liquid chromatography. See Fig. 2: curve 1 is the in vitro transdermal test of clonidine hydrochloride to animal skin, and curve 2 is the permeability experiment (correlation coefficient r=0.9901) of clonidine hydrochloride to cured film, as can be seen from the figure that cured film is to The drug has a linear controlled release effect.

Example 3

Mix 2-butoxyethyl acrylate and N-(1,1-dimethyl-3-oxobutyl)-acrylamide in a mass ratio of 2:8, and then add 5% (w/w) The benzophenone peroxide was dissolved, filtered, and 30ul of the mixed solution was taken, placed on the carrier substrate, spread evenly, and placed in a UV curing apparatus for complete curing.

The obtained cured film was placed in a modified Franz diffusion cell, the supply cell was a methyl salicylate solution, and the receiver cell was a pH 7.4 phosphate buffer. The release rate of methyl salicylate was analyzed by high performance liquid chromatography. See Figure 2: the permeability test of methyl salicylate on the cured film (correlation coefficient r=0.9973), it can be seen from the figure that the cured film has a linear controlled release effect on the drug.

Example 4

Mix 2-butoxy ethyl acrylate and 1,6-hexanediol dimethacrylate in a mass ratio of 4:6, then add 15% (w/w) benzoin propyl ether to dissolve , filter, take 30ul of the mixed solution, put it on the carrier substrate, spread it flat, and place it in a UV curing instrument to cure completely.

Example 5

Mix 2-butoxy ethyl acrylate and 2-carboxy ethyl acrylate in a mass ratio of 7:3, then add 0.1% (w/w) 1-hydroxycyclohexyl phenyl ketone, take 30ul of the mixed solution, and put it in On the carrier substrate, the coating is laid flat, and placed in a UV curing device to cure completely.

Claims (4)

1, a kind of ester group that comprises is partly with the composition of the acrylate of alkoxyl group, and it is characterized in that said composition comprises: (A) a kind of ester group of acrylate is partly with the monomer of alkoxyl group; (B) a kind of acrylate or acrylamide monomer; (C) a kind of light trigger accounts for 0.1%～15% of composition quality; The ratio of monomer A, B can be regulated arbitrarily in the composition.

2,, it is characterized in that the ester group of described acrylate is partly with the monomer general formula CR of alkoxyl group according to the composition of claim 1 ₂R ₁==CR ₃COOR ₄Expression, wherein R ₁, R ₂, R ₃Be any substituting group, comprise-H ,-CH ₃,-C ₆H ₅,-CH=CH ₂,-OH ,-COOH ,-OCH ₃,-SO ₃H ,-NH ₂,-N (CH ₃) ₃Cl, R ₄Be the substituting group that has alkoxyl group, comprise-CH ₂OCH ₃,-(CH ₂) ₂OCH ₃,-(CH ₂) ₃OCH ₃,-(CH ₂) ₄OCH ₃,-(CH ₂) ₅OCH ₃,-CH ₂CH ₂OCH ₃,-CH ₂CH ₂OC ₂H ₅,-CH ₂CH ₂OC ₃H ₇,-CH ₂CH ₂OCH ₂OC ₆H ₅,-C ₂H ₄CH ₂OCH ₃,-C ₂H ₄CH ₂OC ₂H ₅,-C ₃H ₆CH ₂OCH ₃,-C ₃H ₆CH ₂OC ₂H ₅,-C ₃H ₆CH ₂OC ₆H ₅

3,, it is characterized in that described acrylate monomer general formula CR according to the composition of claim 1 ₂R ₁==CR ₃COOR ₄Expression, wherein R ₁, R ₂, R ₃Be any substituting group, comprise-H ,-CH ₃,-C ₆H ₅,-CH=CH ₂,-OH ,-COOH ,-OCH ₃,-SO ₃H ,-NH ₂,-N (CH ₃) ₃Cl; R ₄Substituting group is the group that alkoxyl group replaces, and comprises-(CH ₂) ₂O (CH ₂) ₂CH ₃,-(CH ₂) ₃O (CH ₂) ₂CH ₃,-(CH ₂) ₂O (CH ₂) ₄CH ₃Or the group of alkyl replacement, comprise-(CH ₂) ₃CH ₃,-(CH ₂) ₁₁CH ₃,-CH ₂CH=CH ₂, or the group of ester group replacement, comprise-(CH ₂) ₂OOCCH=CH ₂,-(CH ₂) ₄OOCCH=CH ₂,-(CH ₂) ₆OOCCH=CH ₂, or the group of hydroxyl replacement, comprise-(CH ₂) ₂CH ₂OH ,-(CH ₂) ₃CH ₂OH ,-(CH ₂) ₄CH ₂OH, or the group of carboxyl substituted comprise-(CH ₂) ₂COOH ,-(CH ₂) ₄COOH ,-(CH ₂) ₆COOH; Described acrylamide monomer general formula CR ₂R ₁==CR ₃CONR ₄Expression, wherein R ₁, R ₂, R ₃, R ₄Define identical with acrylate monomer.

4,, it is characterized in that described light trigger is the initiator of the ultraviolet light polymerization that is useful on according to the composition of claim 1.

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