CN102008730B - Transdermal medicine composition and transdermal medicine kit - Google Patents
Transdermal medicine composition and transdermal medicine kit Download PDFInfo
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- CN102008730B CN102008730B CN200910092261XA CN200910092261A CN102008730B CN 102008730 B CN102008730 B CN 102008730B CN 200910092261X A CN200910092261X A CN 200910092261XA CN 200910092261 A CN200910092261 A CN 200910092261A CN 102008730 B CN102008730 B CN 102008730B
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Abstract
The invention provides a transdermal medicine composition which comprises a carrier and active medicine ingredients, wherein the main ingredient of the carrier is crosslinked polyacrylamide, the degree of crosslinking of the crosslinked polyacrylamide is about 0.5-1%, the glass-transition temperature is 110-130 DEG C and 170-185 DEG C, and the aperture of a gel skeleton of the crosslinked polyacrylamide is 5-30 mum. The invention also provides a transdermal medicine kit comprising a micro needle array and the transdermal medicine composition. In the transdermal medicine composition provided by the invention, the crosslinked polyacrylamide used as the main ingredient of the carrier has good swelling performance, the swelled crosslinked polyacrylamide has good skin adhesion performance, and meanwhile, the carrier has good performance to release water soluble medicines. Moreover, the transdermal medicine kit of the invention can increase the transdermal rate of the transdermal medicine composition, and thus, medicines can effectively enter bodies to take more excellent medicinal effects.
Description
Technical field
The present invention relates to a kind of transdermal drug combination preparation and the transdermal drug test kit that comprises this transdermal drug combination preparation.
Background technology
Transdermal administration is a kind of novel painless administering mode, can avoid the liver first-pass effect and the gastrointestinal tract enzymolysis of traditional administering mode, realizes the drug release of constant speed long time, and the blood drug level that is not prone to injection and oral administration reaches the peak phenomenon.Gel preparation and cataplasma are the common dosage forms type of transdermal administration; But cataplasma only is suitable for the transdermal administration of small-molecular weight medicine at present; And the transdermal penetrating agent that adds in the cataplasma has certain zest to skin; Therefore be prone to cause side reactions such as allergy, exploitation has better transdermal efficient and is suitable for various molecular weight drug transdermals transmission and biocompatibility excellent drug gel preparation substrate and is of great importance for transdermal administration.
Hydrogel be a kind of can be in water remarkable swelling but form after the undissolved polymers swell, have excellent biological compatibility, hydrophilic micromolecule and macromolecular complex mass-energy therefrom freely spread.Hydrogel is widely used in the carrier of hydrophilic medicament, compares with hydrophobic polymer, and a little less than the interaction of the enzyme of hydrogel load and protein isoreactivity material, the biological activity of medicine is held time longer.
Polyacrylamide is the good high polymer of a kind of water solublity; Its HMW and super high molecular weight polymer are widely used in flocculating agent, water treatment, oil extraction, weaving, papermaking and food service industry etc.; For example CN 1446851A discloses a kind of purifying agent of polyacrylamide with very high molecular, and its main component is a polyacrylamide with very high molecular, wherein; The cationic degree of this polyacrylamide with very high molecular is up to 45～70%, and molecular weight is 2,000 ten thousand～25,000,000.In addition, Chinese patent CN 1232548C adopts the mode of aqueous solution polymerization, and to have synthesized molecular weight be 2～120,000 polyacrylamide through adding chain-transferring agent, but it can not form gel, is mainly used in macromolecule emulsifier and binding agent.
As adding a certain amount of bifunctional monomer when the acrylamide polymerization, obtain having the polyacrylamide polymers of certain degree of cross linking, this polymer can form hydrogel in water under constant weight concentration, can be used for the gel-type vehicle of water soluble drug.At present; Water soluble oxidized reduction system initiated polymerization is basically all adopted in preparation (for example Chinese patent CN1068612C, CN 1058639C and CN 1450118A) for medical cross-linked polyacrylamide gel; Later stage adopts the method for organic solvent extraction to remove unreacted monomer; Complex disposal process, and the polymer that obtains is mainly used in tissue filling, and can not be used for transdermal administration.
Summary of the invention
The objective of the invention is to overcome the shortcoming that existing PAAG is not suitable for transdermal administration; A kind of transdermal drug combination preparation and the transdermal drug test kit that comprises this transdermal drug combination preparation are provided; The gel of processing with this transdermal drug combination preparation has good swelling behavior and medicine-releasing performance, is applicable to transdermal administration.
The invention provides a kind of transdermal drug combination preparation; This transdermal drug combination preparation contains carrier and active constituents of medicine; Wherein, The main component of said carrier is crosslinked polyacrylamide, and the glass transition temperature of the polyacrylamide that this is crosslinked is 110～130 ℃ and 170～180 ℃, and the aperture of the gel skeleton of the polyacrylamide that this is crosslinked is 5～30 μ m.
The degree of cross linking of said crosslinked polyacrylamide is approximately 0.5%～1%.
In the transdermal drug combination preparation of the present invention, can also further contain non-ionic surface active agent in the said carrier, and the weight ratio of crosslinked polyacrylamide and non-ionic surface active agent is 1～3: 1.Said non-ionic surface active agent is the mixture of polyethylene glycol type non-ionic surface active agent and sorbitan ester type non-ionic surface active agent, and wherein the weight ratio of polyethylene glycol type non-ionic surface active agent and sorbitan ester type non-ionic surface active agent is 1～4: 2.
In the transdermal drug combination preparation of the invention described above, the weight ratio of said carrier and said active constituents of medicine is 1～200: 1.
In transdermal drug combination preparation of the present invention; Said crosslinked polyacrylamide is that the method through precipitation polymerization prepares; This method is included under the precipitation polymerization condition; Acrylamide monomer and cross-linking agent are contacted in the presence of initiator and first solvent, and said first solvent is for dissolving the organic solvent of acrylamide monomer and cross-linking agent.The condition of said contact comprises that the consumption of cross-linking agent is 0.5～1 mole of % of acrylamide monomer and cross-linking agent sum total amount; The consumption of said initiator is acrylamide monomer and cross-linking agent sum total amount 0.5～1 mole ‰; The weight ratio of said first solvent and acrylamide monomer and cross-linking agent sum total amount is 3～5: 1; The temperature of contact is 55～65 ℃, and the time of contact is 24～36 hours.
Said cross-linking agent is selected from methylene diacrylamide, piperazine bisacrylamide, N, N '-dihydroxy ethyl bisacrylamide, N, at least a in the group that N '-ethylene bisacrylamide etc. is formed.
Said initiator is selected from least a in the group that azodiisobutyronitrile, ABVN, benzoyl peroxide, dibenzoyl peroxide, the benzoyl peroxide tert-butyl ester, methyl ethyl ketone peroxide etc. are formed.
Said first solvent is selected from least a in the group that acetone, butanone, methyl amylketone, methyl iso-butyl ketone (MIBK), Ketohexamethylene, methanol, ethanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol etc. are formed.
In the process of above-mentioned precipitation polymerization; Can also further in said first solvent, add the unsaturated carboxylic acid that carbon-carbon double bond has polymerization activity, the amount that the carbon-carbon double bond of interpolation has the unsaturated carboxylic acid of polymerization activity is 10～15 moles of % of acrylamide monomer and cross-linking agent sum total amount.And; After the method for said precipitation polymerization also is included in the precipitation polymerization completion; Isolate the crosslinked polyacrylamide solid of contact gained; With this crosslinked polyacrylamide solid of second organic solvent washing, said second organic solvent does not dissolve crosslinked polyacrylamide solid, but can dissolve acrylamide monomer and cross-linking agent then.
In the transdermal drug combination preparation of the present invention, said carrier can be powder type, also can be for containing the hydrogel of crosslinked polyacrylamide, and said active constituents of medicine is dispersed in this hydrogel that contains crosslinked polyacrylamide.Wherein, the crosslinked polyacrylamide content in the said hydrogel that contains crosslinked polyacrylamide is 2.5～5 weight %.
In transdermal drug combination preparation of the present invention, said active constituents of medicine is the water soluble drug that is used for transdermal administration, in particular for pharmaceutical grade protein, polypeptide drugs or the genomic medicine of transdermal administration.
The present invention also provides a kind of transdermal drug test kit, and wherein, this test kit comprises microneedle array and above-mentioned transdermal drug combination preparation provided by the invention.
In transdermal drug combination preparation provided by the invention; Swelling behavior as the crosslinked polyacrylamide of carrier main component is good; Only need before administration, active constituents of medicine and this support powder to be mixed with water; Can form a kind of gel preparation fast, therefore need not estimate the stability of gel preparation in storage process, not only can reduce research and production cost like this; Also can avoid the long-time perhaps variation of other composition character of gel preparation Chinese medicine active component that is caused that stores, also can be convenient to the adjusting of dosage simultaneously.
And; Has the good skin bond properties after the carrier swelling of the present invention; Excellent adhesiveness can be provided when transdermal administration, because the glass transition temperature of the crosslinked polyacrylamide in the carrier is 110～130 ℃ and 170～180 ℃, the molecular weight that has embodied polyacrylamide strand in this crosslinked polyacrylamide to a certain extent is lower simultaneously; And carry out lyophilization after the formation gel; The polyacrylamide skeleton crosslinked through scanning electron microscopic observation presents cellular, and the gel skeleton aperture is 5～30 μ m, and therefore carrier of the present invention is good to the release performance of water soluble drug.In an embodiment, above-mentioned support powder and bovine serum albumin are mixed with gel preparation, carry out the transdermal test in vitro experiment, the result shows that this gel preparation has excellent drug release effect.
In addition, because acrylamide monomer has stronger neurotoxicity, therefore in final resulting polymers, need the monomeric content of strict control.In crosslinked Preparation of Polyacrylamide process of the present invention, through the employing precipitation polymerization method, and select appropriate solvent for use, can effectively control the said crosslinked polyacrylamide that is met requirement of the present invention; And; Because monomer is prone in first solvent, dissolve; Only need after polyreaction is accomplished repeatedly to wash and to remove most of monomer, make the content of monomer in the polymer be reduced to desired below the mark with first solvent or any solvent that can dissolve acrylamide monomer but can not dissolve polyacrylamide.With remove monomer methods with organic solvent extraction in the prior art and compare, it is simple to remove poisonous monomeric process, and cost is lower.
Generally, because the inhibition of keratodermatitis, pharmaceutical grade protein, polypeptide drug or genomic medicine are difficult for seeing through skin and get in the body.Adopt the micropin medicine-feeding technology; On the horny layer of skin, form small medicine transmission path; Can make the transdermal transmission of pharmaceutical grade protein, polypeptide drug or genomic medicine more easy; Therefore combine the test kit of the transdermal drug combination preparation of microneedle array and the invention described above can improve the skin permeation rate of transdermal drug combination preparation of the present invention, thereby medicine is effectively got in the body and the more excellent drug effect of realization.
Description of drawings
Fig. 1 is the stereoscan photograph of the crosslinked polyacrylamide powder of the embodiment of the invention 2.
The stereoscan photograph of gel after lyophilization that Fig. 2 processes for the crosslinked polyacrylamide of the embodiment of the invention 2.
The stereoscan photograph of gel after lyophilization that Fig. 3 processes for the crosslinked polyacrylamide of A in the Comparative Examples 1 of the present invention.
Fig. 4 is the curve chart of bovine serum albumin transdermal release effect in the gel preparation of the embodiment of the invention 10～16 and Comparative Examples 3.
Fig. 5 is the curve chart of bovine serum albumin transdermal release effect in the gel preparation of the embodiment of the invention 11,17～22 and Comparative Examples 3.
The specific embodiment
Pairing temperature when used term " glass transition temperature " refers to that polymer changes in this description between glassy state and elastomeric state.The glass transition temperature of crosslinked polyacrylamide is measured through differential scanning calorimetry (DSC) among the present invention, and its concrete measuring method has been conventionally known to one of skill in the art.There is the reason of two glass transition temperatures in crosslinked polyacrylamide among the present invention, possibly be that the transformation of glassy state to elastomeric state takes place under different temperature respectively for it owing to there are two kinds of different amorphous states in the polymer.
In this description used term " ionic strength " equal in the solution every kind of ionic molality multiply by this ionic valence mumber square, each item sum of gained half the represented with I usually.It has expressed the degree of the electrical power of effects of ion.
The invention provides a kind of transdermal drug combination preparation; This transdermal drug combination preparation contains carrier and active constituents of medicine, and wherein, the main component of said carrier is crosslinked polyacrylamide; The degree of cross linking of the polyacrylamide that this is crosslinked is approximately 0.5%～1%; Glass transition temperature is 110～130 ℃ and 170～180 ℃, is preferably 117～120 ℃ and 175～182 ℃, and the aperture of the gel skeleton of the polyacrylamide that this is crosslinked is 5～30 μ m; Be preferably 12～30 μ m, further be preferably 15～30 μ m.
The aperture of said gel skeleton is for after being mixed and made into hydrogel with crosslinked polyacrylamide powder and water; In the lyophilization cold-trap, be lower than 10ppm, the bore dia that then sample after this lyophilization is arrived through scanning electron microscopic observation at about 8 hours of-50 ℃ of following lyophilizations water content in sample.
The proportioning of carrier and active constituents of medicine can change in a big way, and the weight ratio of preferred said carrier of the present invention and said active constituents of medicine is 0.5～500: 1, further is preferably 1～200: 1, further is preferably 2～150: 1.Specifically look concrete active constituents of medicine and required dosage and decide.
The crosslinked polyacrylamide that satisfies above-mentioned condition can obtain through the whole bag of tricks, can be polymerization single polymerization monomer with the acrylamide for example, with methylene diacrylamide as cross-linking agent and polymerization obtains.Although it is a variety of that polymeric method has; For example; Water solution polymerization process and emulsion polymerization, still, because the polymerization activity of acrylamide monomer is bigger; The acrylamide polymer molecular weight that adopts solution polymerization process and emulsion polymerization to obtain is very big, is difficult to form the ideal gel that is applicable to transdermal administration.On the contrary; Inventor of the present invention finds, is employed in the organic solvent sedimentary method and carries out polymerization, because the dissolubility of acrylamide monomer in organic solvent is bigger; And polymer dissolubility in organic solvent is very little; When polymer molecular weight greatly to a certain degree will from solvent, being precipitated out, can not continue polymerization again, therefore use sedimentary method; Consumption through control cross-linking agent and initiator can effectively be controlled the molecular weight and the degree of polymerization of crosslinked polyacrylamide, thereby can obtain crosslinked polyacrylamide required for the present invention.Obtain crosslinked polyacrylamide with the above-mentioned characteristic of the present invention therefore for ease, effectively, among the present invention, said crosslinked polyacrylamide is through the method preparation of precipitation polymerization.Another advantage for preparing through precipitation polymerization process simultaneously is that monomer is prone in reaction dissolvent, dissolve, and only need repeatedly wash the crosslinked polyacrylamide that obtains with reaction dissolvent after reaction is accomplished and can remove monomer.
The method for preparing above-mentioned crosslinked polyacrylamide in the present invention is specially; Under the precipitation polymerization condition; Acrylamide monomer and cross-linking agent are contacted in the presence of initiator and first solvent, and said first solvent is for dissolving acrylamide monomer and cross-linking agent and not dissolving the organic solvent of crosslinked polyacrylamide.Said cross-linking agent is a bisacrylamide class cross-linking agent, can comprise methylene diacrylamide, piperazine bisacrylamide, N, N '-dihydroxy ethyl bisacrylamide, N, one or more in N '-ethylene bisacrylamide.Under the preferable case, the cross-linking agent that uses in the above-mentioned polymerization process is methylene diacrylamide.Through regulating the different content of methylene diacrylamide; Obtain a series of polymer with different degrees of cross linking; Estimate its swelling behavior; Finding when the addition of methylene diacrylamide accounts for 0.5～1 mole of % of acrylamide monomer and methylene diacrylamide total amount, is colourless gel after the better and polymers swell of the swelling behavior of polymer.Preferably, the condition of above-mentioned precipitation polymerization comprises: the consumption of cross-linking agent is 0.2～1.5 mole of % of acrylamide monomer and cross-linking agent total amount, is preferably 0.5～1 mole of %, more preferably 0.6～0.8 mole of %; The consumption of said initiator is monomer and cross-linking agent total amount 0.3～1.5 mole ‰, is preferably 0.5～1 mole ‰, more preferably 0.6～0.75 mole ‰; The weight ratio of said first solvent and monomer and cross-linking agent total amount is 3～5: 1, is preferably 3.5～4.5: 1; The temperature of contact is 55～65 ℃, is preferably 60～64 ℃; The time of contact is 24～36 hours, is preferably 26～30 hours.
In order to obtain to satisfy simultaneously the polyacrylamide in above-mentioned vitrification point and gel skeleton aperture, first solvent that in above-mentioned polymeric process, uses is the mixture of ketones solvent or alcohols solvent or ketones solvent and alcohols solvent.Wherein, said ketones solvent comprises one or more in acetone, butanone, methyl amylketone, methyl iso-butyl ketone (MIBK), the Ketohexamethylene, and said alcohols solvent comprises one or more in methanol, ethanol, normal propyl alcohol, isopropyl alcohol, the n-butyl alcohol.Satisfy the polyacrylamide in above-mentioned preferred glass temperature and preferred gel skeleton aperture simultaneously for further acquisition, preferably, said ketones solvent is an acetone, and said alcohols solvent is an ethanol.Further under the preferable case, first solvent of the present invention is an acetone.
The preferred oil-soluble initiator that uses comes initiated polymerization in above-mentioned polymeric process.Said oil-soluble initiator is an azo-initiator, for example azodiisobutyronitrile and/or ABVN; Or peroxide initiator, for example one or more in benzoyl peroxide, dibenzoyl peroxide, the benzoyl peroxide tert-butyl ester, the methyl ethyl ketone peroxide.In preferred implementation of the present invention, said initiator is an azodiisobutyronitrile.
In order to make said carrier have good swelling behavior and adhesion property, preferably, in polymerization process, in first solvent, add the unsaturated carboxylic acid class material that carbon-carbon double bond has polymerization activity, so that contain carboxyl in the polymer chain.The unsaturated carboxylic acid class material that above-mentioned carbon-carbon double bond has a polymerization activity preferably carbon number is 3～20 olefin(e) acid; Further preferably carbon number is 3～10 olefin(e) acid; Said olefin(e) acid can be one or more in substituted or unsubstituted straight-chain carboxylic acid, substituted or unsubstituted branched carboxylic acids, the substituted or unsubstituted olefin(e) acid that contains aromatic ring, the present invention further the unsaturated carboxylic acid of preferred said carbon-carbon double bond with polymerization activity be that acrylic acid, methacrylic acid, 2-butylene acid, 3-butenoic acid, propylene halide are sour, right-hydroxy-cinnamic acid, in the penetenoic acid one or more.Under the special preferable case, in polymerization process of the present invention, use acrylic acid and/or methacrylic acid.Through regulating the content that above-mentioned carbon-carbon double bond in the monomer has the unsaturated carboxylic acid class material of polymerization activity, can make carrier of the present invention equal swelling fast in the aqueous solution of different ionic strengths and different pH.In preferred implementation of the present invention; The olefin(e) acid class material that contains 5～20 moles of % of total monomer amount in first solvent; Be preferably 10～15 moles of %; More preferably 11～13 moles of % make resulting carrier have good swelling behavior, and have good adhesion property by the gel preparation of this preparing carriers.
Because the polyacrylamide amine monomers has stronger neurotoxicity, therefore in final resulting polymers, need the monomeric content of strict control.Among the present invention; The method of control content of monomer can be carried out solid-liquid separation for the product after will contacting; Isolate crosslinked polyacrylamide solid wherein; Repeatedly wash with second organic solvent then, it is desired below the mark that content of monomer in the crosslinked polyacrylamide solid is reduced to, and said second organic solvent is for dissolving acrylamide monomer but can not dissolve all kinds of solvents of polyacrylamide.Preferably, said second organic solvent is the mixture of ketones solvent or alcohols solvent or ketones solvent and alcohols solvent.Wherein, said ketones solvent comprises one or more in acetone, butanone, methyl amylketone, methyl iso-butyl ketone (MIBK), the Ketohexamethylene, and said alcohols solvent comprises one or more in methanol, ethanol, normal propyl alcohol, isopropyl alcohol, the n-butyl alcohol.Said second organic solvent and first solvent can be identical or different.Preferred said second organic solvent is an ethanol.Among the present invention, the detection method according to standard GB/T12005.4-89 detects residual monomer content, and content of monomer accounts for 0.000001～0.000002% of polyacrylamide total amount as a result, far below country and international standard.
In order further to improve the medicine-releasing performance and the dermal osmosis performance of the gel preparation that makes, in transdermal drug combination preparation of the present invention, said carrier preferably also contains non-ionic surface active agent.Although various non-ionic surface active agents all can improve the medicine-releasing performance and the dermal osmosis performance of the gel preparation that makes to some extent; But inventor of the present invention finds; When non-ionic surface active agent is the mixture of polyethylene glycol type non-ionic surface active agent and sorbitan ester type non-ionic surface active agent; The medicine-releasing performance of gel preparation and dermal osmosis performance are significantly improved; Particularly the weight ratio when polyethylene glycol type non-ionic surface active agent and sorbitan ester type non-ionic surface active agent is 1～4: 2 preferred 2～4: in the time of 2; The medicine-releasing performance of this gel preparation and dermal osmosis performance are for example independent polyethylene glycol type non-ionic surface active agent of other non-ionic surface active agent or independent more than 2～3 times of sorbitan ester type non-ionic surface active agent; Be when not containing non-ionic surface active agent more than 6～8 times; Therefore, also to contain weight ratio be 1～4: 2 further preferred 2～4: 2 polyethylene glycol type non-ionic surface active agent and the mixture of sorbitan ester type non-ionic surface active agent to the preferred especially said carrier of the present invention.Said polyethylene glycol type non-ionic surface active agent is preferably the Polyethylene Glycol of molecular weight between 200～10000, like PEG-200, PEG-400, PEG-800, PEG-2000 etc.; Said sorbitan ester type non-ionic surface active agent is preferably one or more in Si Pan or the tween surfactants, like Span-20, Span-40, Span-80 and Tween-20, Tween-40, Tween-80 etc.In an embodiment of the invention, the preferred especially said non-ionic surface active agent mixture that is PEG-200 and Tween-20.
Preferably in said carrier, the mass ratio of crosslinked polyacrylamide and non-ionic surface active agent total amount is 1～5: 1 is preferably 1～3: 1.Under the further preferred situation; Crosslinked polyacrylamide: polyethylene glycol type non-ionic surface active agent: the mass ratio of sorbitan ester type non-ionic surface active agent is 2.5: 1: 1 to 5: 1: 1, and further preferred crosslinked polyacrylamide: the polyethylene glycol type non-ionic surface active agent: the mass ratio of sorbitan ester type non-ionic surface active agent is 3: 1: 1 to 4: 1: 1.Employed nonionic surfactant is medicinal rank among the present invention, can in the administration process, not produce toxic and side effects, and when being used for pharmaceutical grade protein, polypeptide drug or genomic medicine, can not change the character of medicine.
The above-mentioned carrier that contains crosslinked polyacrylamide and non-ionic surface active agent can make through the whole bag of tricks; Preferably; According to the above-mentioned crosslinked polyacrylamide and the mass ratio of non-ionic surface active agent total amount, the non-ionic surface active agent of being selected for use is used dissolve with ethanol, add of the present invention crosslinked polyacrylamide powder with the precipitation polymerization process preparation; Add a large amount of ethanol then and stir, vapor away the powder that ethanol promptly obtains said carrier.
In transdermal drug combination preparation of the present invention, said active constituents of medicine can be the various water soluble drug that is used for transdermal administration, especially pharmaceutical grade proteins, polypeptide drug or genomic medicine; And this active constituents of medicine can be various forms.Said active constituents of medicine can be liquid preparation, also can be powder formulation.The content of said active constituents of medicine can change according to various medication demand.In transdermal drug combination preparation of the present invention, the weight ratio of preferred said carrier and said active constituents of medicine is 0.5～500: 1, further is preferably 1～200: 1, further is preferably 2～150: 1.
In transdermal drug combination preparation of the present invention, said carrier is preferably powder type.In use; Earlier a certain amount of active constituents of medicine is mixed with the two fun gi polysaccharides aqueous solution by the medication demand; Take by weighing a certain amount of support powder again, in said support powder, add the gel preparation of the aqueous solution of active constituents of medicine, perhaps drug powder is mixed with support powder and add the gel preparation of entry again with the preparation medicine with the preparation medicine; Thereby in the gel preparation of medicine, active constituents of medicine is dispersed in the hydrogel of carrier formation.With this gel preparation total amount is benchmark, and the content of said crosslinked polyacrylamide is 2.5～5 weight %.When the content of said crosslinked polyacrylamide was lower than 2.5 weight %, formed gel mobile big was unfavorable for being applied to transdermal administration; When the content of said crosslinked polyacrylamide was higher than 5 weight %, the medicine-releasing performance of formed gel descended to some extent.Under the preferable case, be benchmark with this gel preparation total amount further, the content of said crosslinked polyacrylamide is 3～4 weight %.
Carrier in the transdermal drug combination preparation of the present invention can be processed powder type earlier; The quick swelling of ability after adding aqueous solution; Before administration, only need the aqueous solution of two fun gi polysaccharides active component is added in this support powder, perhaps pulverous medicine is mixed with water with pulverous carrier, can form a kind of drug gel preparation fast; Therefore need not consider the stability of gel preparation in storage process; Not only can reduce research and production cost, also can avoid the long-time perhaps variation of other composition character of gel preparation Chinese medicine that is caused that stores, also can be convenient to the adjusting of dosage simultaneously.
The swelling rate of the carrier among the present invention is very fast, all can quick swelling in the aqueous solution of different ionic strengths and different pH.When the preparation gel preparation; Only need take by weighing a certain amount of above-mentioned support powder; The aqueous solution that adds the active constituents of medicine of 20～40 times of its weight; Perhaps support powder is mixed with active constituents of medicine earlier, add the aqueous solution of 20～40 times of its weight, can in 1～2 minute, rapid swelling become gel state.
In the transdermal drug combination preparation of the present invention; Described carrier has the good skin bond properties later in swelling; Excellent adhesiveness can be provided when transdermal administration, because the degree of cross linking of the crosslinked polyacrylamide that is wherein contained is approximately 0.5%～1%, glass transition temperature is 110～130 ℃ and 170～180 ℃ simultaneously; The molecular weight that has embodied polyacrylamide strand in this crosslinked polyacrylamide to a certain extent is lower; And carrier of the present invention is formed gel carry out lyophilization afterwards, through scanning electron microscopic observation, this crosslinked polyacrylamide skeleton is cellular; The gel skeleton aperture is 5～30 μ m, explains that carrier of the present invention has good medicine-releasing performance.In preferred implementation of the present invention, use bovine serum albumin or insulin as active constituents of medicine, be mixed with the drug gel preparation with said support powder, carry out the transdermal test in vitro result of experiment and show that this gel preparation has excellent drug release effect.
And employing micropin medicine-feeding technology; On the horny layer of skin, form small medicine transmission path; The transdermal transmission of the pharmaceutical grade protein that can make, polypeptide drug or genomic medicine is more easy; Therefore the present invention also provides a kind of transdermal drug test kit, and this test kit comprises the transdermal drug combination preparation of microneedle array and the invention described above.Said microneedle array can be a various microneedle array of the prior art, and wherein, the cross sectional shape of micropin can be conical or polyhedral cone shaped, and the micropin height can be between 50～400 microns, and the needle point diameter can be between 100 nanometers～10 micron.The material of said microneedle array can be various materials, for example can be rustless steel micropin, metal micro-needle, glass micropipette, silicon pin or with the integrated degradable micropin of macromolecular material.Transdermal drug test kit of the present invention can improve the skin permeation rate of transdermal drug combination preparation of the present invention, thereby medicine is effectively got in the body and realizes more excellent drug effect.
Below in conjunction with some specific embodiments, further specify content of the present invention.
Embodiment 1～8
Acrylamide and methylene diacrylamide, acrylic acid and initiator azodiisobutyronitrile are joined in the 100ml there-necked flask according to the described amount of table 1; (the first used solvent is an acetone to first solvent of adding 50ml among the embodiment 1～7; The first used solvent is an isopropyl alcohol among the embodiment 8), load onto thermometer and reflux and mechanical stirring device, be warming up to 64 ℃ of back flow reaction under the nitrogen protection 30 hours; After sucking filtration removes and desolvates; With washing with alcohol purification resulting polymers, the content that records acrylamide monomer in the crosslinked polyacrylamide that is making until the detection method with standard GB/T12005.4-89 is lower than 0.000002%, then 120 ℃ of following vacuum dryings 24 hours; Obtain crosslinked polyacrylamide powder, list in table 1 in their glass transition temperature, the degree of cross linking and gel skeleton aperture.(methylene diacrylamide/total monomer amount ≈ degree of cross linking adopts reaction condition reaction of the present invention more than 24 hours, and monomer conversion reaches more than 99%.)
Table 1
| Methylene diacrylamide/total monomer (mol/mol) | Acrylic acid/total monomer (mol/mol) | Azodiisobutyronitrile/total monomer (mol/mol) | The glass transition temperature of crosslinked polyacrylamide | The degree of cross linking | The aperture of gel skeleton (μ m) | |
| Embodiment 1 | 0.5/100 | 10％ | 0.5‰ | 117℃，175℃ | 0.5％ | 15～25 |
| |
0.75/100 | 12.5％ | 0.75‰ | 118.2℃，178℃ | 0.75％ | 15～30 |
| Embodiment 3 | 1.0/100 | 15％ | 1‰ | 119.4℃，180.6℃ | 1.0％ | 12～25 |
| |
0.75/100 | 0 | 0.75‰ | 117.3℃，176.2℃ | 0.75％ | 10～28 |
| Embodiment 5 | 0.75/100 | 20％ | 0.75‰ | 118.5℃，179.4℃ | 0.75％ | 10～22 |
| |
1.5/100 | 12.5％ | 0.75‰ | 117.9℃，178.6℃ | 1.5％ | 8～20 |
| Embodiment 7 | 0.75/100 | 12.5％ | 1.5‰ | 120℃，182℃ | 0.75％ | 5～15 |
| |
0.75/100 | 12.5％ | 0.75‰ | 130℃，185℃ | 0.75％ | 5～20 |
| Comparative Examples 1 | - | - | - | 203.5℃ | - | ＜1 |
Crosslinked polyacrylamide powder to above-mentioned synthetic embodiment 1～8 carries out the swellability experiment.Take by weighing crosslinked each 0.38g of polyacrylamide powder of embodiment 1～8; Add 10ml water; And the Glass rod of the about 6mm of diameter that the lower end is slick and sly is contained on the agitator, agitator, and making its speed is 60r/min; And make its Glass rod be inserted in sample central authorities, when sample is their complete swelling formation needed time of gel along the time that Glass rod begins rising (pole-climbing).The result of swelling time shows in table 2.Experimental result finds that embodiment 1～3 all can form gel in pH 3～9 scopes and ionic strength 0.1～1mol/kg scope, and the swelling rate of embodiment 2 is faster than embodiment 1 and 3, and gel is the pellucidity with viscosity after the swelling.Embodiment 4～7 can only can form gel in pH 4～8 scopes and ionic strength 0.1～0.5mol/kg scope, and swelling time is slower than embodiment 1～3, a little less than the gel viscosity of formation.The swelling of the crosslinked polyacrylamide powder of embodiment 5～7 is more slow.Among the embodiment 8 owing to use isopropyl alcohol as first solvent; Therefore the crosslinked polyacrylamide that forms is compared with the crosslinked polyacrylamide of embodiment 2; Glass transition temperature is high slightly, swelling rate is slower, thereby the present invention preferably uses acetone as first solvent.
Table 2
| The embodiment numbering | Embodiment 1 | |
Embodiment 3 | |
Embodiment 5 | |
Embodiment 7 | |
Comparative Examples 1 |
| Swelling time (minute) | 0.75 | 0.5 | 1 | 2 | 5.5 | 7.8 | 13.2 | 12 | ＞30 |
Comparative Examples 1
The crosslinked polyacrylamide of the aqueous solution polymerization of learning from else's experience preparation (press embodiment 1 described method prepares among the CN1068612C, process vacuum drying powder) (below be called A), the glass transition temperature of A is seen table 1.
Take by weighing A powder 0.38g, add 10ml water, the method described in the embodiment 1～8 of pressing is measured its complete swelling and is formed the needed time of gel.The result is as shown in table 2, the swelling time of A＞30 minute.
The result shows; Compare with the swelling time of embodiment 1～8; The swelling time of A is longer; The swelling rate of crosslinked polyacrylamide is all less than 2 minutes in the embodiments of the invention 1～3, and the swelling rate that the crosslinked polyacrylamide that makes among the present invention is described is faster than the swelling rate of the crosslinked polyacrylamide through the aqueous solution polymerization preparation of the prior art.
Embodiment 9
Get the crosslinked polyacrylamide powder of 0.038g the foregoing description 1～8 respectively; Add the 1ml aqueous solution; Treat that its swelling becomes after the gel; In the lyophilization cold-trap, be lower than 10ppm at about 8 hours of-50 ℃ of lyophilizations water content in sample, carry out scanning electron microscopic observation, these gels are listed in table 1 through the skeleton aperture after the lyophilization.Fig. 2 shows the skeleton drawing of gel after lyophilization that the crosslinked polyacrylamide powder of embodiment 2 forms.
The result shows that observe polyacrylamide skeleton crosslinked in these gels when amplifying 600 times and be cellular, the skeleton aperture is 5～30 μ m.The skeleton aperture that forms behind the gel by the crosslinked polyacrylamide powder of the embodiment 1～3 of optimum condition preparation is 12～30 μ m.
Comparative Examples 2
Get the A powder in the 0.038g Comparative Examples 1, add the 1ml aqueous solution, treat that its swelling becomes after the gel, in the lyophilization cold-trap, be lower than 10ppm at about 8 hours of-50 ℃ of lyophilizations water content in sample, carry out scanning electron microscopic observation, the result sees Fig. 3.The aperture of crosslinked polyacrylamide skeleton is amplified 1800 times and is not observed tangible hole much smaller than 1 μ m in this gel.
Fig. 3 is compared with Fig. 2, and the aperture of obviously finding out crosslinked polyacrylamide skeleton of the present invention is much larger than the aperture of the skeleton of crosslinked polyacrylamide of the prior art, and structure rule very, more helps the release of protein, polypeptide or genomic medicine.
Embodiment 10～22
The crosslinked polyacrylamide powder of the foregoing description 1～7 is become different transdermal gel preparations according to table 3 formulated, and (it is the percentage by weight of benchmark that each constituent content is with the gel preparation total amount; Remaining part is the content of pure water); Wherein containing bovine serum albumin concentration is that (the bovine serum albumin molecular weight is 67kD to the 2mg/g gel; Can find out that from scanning electron microscope picture 2 the gel skeleton aperture is much larger than the size of range protein, thereby can be suitable for the release of protein, polypeptide or the genomic medicine of various molecular weight); Through the auxiliary mode of micropin, use microneedle array to act on area and be 1cm
2Skin (484 holes) 30s after; The aqueogel that respectively embodiment 10～22 of 300mg is made is coated on the micropin site of action; Use the upright jacket type diffusion cell of classical Franz; Estimate in the different preparations bovine serum albumin to the permeability (adopting fluorescently-labeled bovine serum albumin) of rat skin in vitro through fluorescence spectrum method for measuring bovine serum albumin concentration.Bovine serum albumin accumulation transit dose is in time seen Fig. 4 in the different preparations.
Table 3
| Crosslinked polyacrylamide powder source | Crosslinked polyacrylamide amine content | PEG-200 content | Tween-20 content | |
| Embodiment 10 | Embodiment 1 | 3.8％ | ?1％ | 1％ |
| Embodiment 11 | |
3.8％ | ?1％ | 1％ |
| Embodiment 12 | Embodiment 3 | 3.8％ | ?1％ | 1％ |
| Embodiment 13 | |
3.8％ | ?1％ | 1％ |
| Embodiment 14 | Embodiment 5 | 3.8％ | ?1％ | 1％ |
| Embodiment 15 | |
3.8％ | ?1％ | 1％ |
| Embodiment 16 | Embodiment 7 | 3.8％ | ?1％ | 1％ |
| Embodiment 17 | |
2.5％ | ?0.83％ | 1.67％ |
| Embodiment 18 | |
5％ | ?1.1％ | 0.55％ |
| Embodiment 19 | |
8％ | ?1％ | 1％ |
| Embodiment 20 | |
3.8％ | ?0 | 1％ |
| Embodiment 21 | |
3.8％ | ?1％ | 0 |
| Embodiment 22 | |
3.8％ | ?0 | 0 |
| Comparative Examples 3 | Comparative Examples 1 | 3.8％ | ?1％ | 1％ |
Comparative Examples 3
By the prescription in the table 3 the sample A in the Comparative Examples 1 is mixed with gel preparation, the method described in the embodiment 10～22 of pressing detects bovine serum albumin in this gel preparation to the permeability of rat skin in vitro.Bovine serum albumin accumulation transit dose is in time seen Fig. 4 and Fig. 5 in this gel preparation.
As shown in Figure 4; The gel preparation of embodiment 10～16 is compared bovine serum albumin cumulant in time with the gel preparation of A more, and the medicine-releasing performance that Percutaneously administrable prepn of the present invention is described is better than the medicine-releasing performance of crosslinked PAHG of the prior art.
As shown in Figure 5; The gel preparation of embodiment 11,17,18 and the embodiment that only contains a kind of surfactant 20,21 or do not contain gel preparation among the embodiment 22 of surfactant to compare bovine serum albumin cumulant in time more explain that Percutaneously administrable prepn of the present invention adds the polyethylene glycol type non-ionic surface active agent simultaneously and sorbitan ester type non-ionic surface active agent has excellent especially transdermal performance.But after crosslinked polyacrylamide powder was greater than 5%, the transdermal performance of gel preparation descended (embodiment 19) to some extent, but all good than the Comparative Examples that adds two kinds of surfactants simultaneously 3, explained that transdermal medicine preparation of the present invention has excellent medicine-releasing performance.
Claims (16)
1. transdermal drug combination preparation; This transdermal drug combination preparation contains carrier and active constituents of medicine; It is characterized in that: the main component of said carrier is crosslinked polyacrylamide; The glass transition temperature of the polyacrylamide that this is crosslinked is 110～130 ℃ and 170～185 ℃, and the aperture of the gel skeleton of the polyacrylamide that this is crosslinked is 5～30 μ m;
Said crosslinked polyacrylamide is that the method through precipitation polymerization prepares, and this method is included under the precipitation polymerization condition, and acrylamide monomer and cross-linking agent are contacted in the presence of initiator and first solvent; Said first solvent is for dissolving the organic solvent of acrylamide monomer and cross-linking agent.
2. transdermal drug combination preparation according to claim 1 wherein, also contain non-ionic surface active agent in the said carrier, and the weight ratio of crosslinked polyacrylamide and non-ionic surface active agent is 1～3: 1.
3. transdermal drug combination preparation according to claim 1 and 2, wherein, the weight ratio of said carrier and said active constituents of medicine is 1～200: 1.
4. transdermal drug combination preparation according to claim 2; Wherein, Said non-ionic surface active agent is the mixture of polyethylene glycol type non-ionic surface active agent and sorbitan ester type non-ionic surface active agent, and wherein the weight ratio of polyethylene glycol type non-ionic surface active agent and sorbitan ester type non-ionic surface active agent is 1～4: 2.
5. transdermal drug combination preparation according to claim 3, wherein, said carrier is a powder type.
6. transdermal drug combination preparation according to claim 3, wherein, said carrier is the hydrogel that contains crosslinked polyacrylamide, said active constituents of medicine is dispersed in this hydrogel that contains crosslinked polyacrylamide.
7. transdermal drug combination preparation according to claim 6, wherein, the content of crosslinked polyacrylamide in the said hydrogel that contains crosslinked polyacrylamide is 2.5～5 weight %.
8. according to claim 1,2,6 or 7 described transdermal drug combination preparations, wherein, the degree of cross linking of said crosslinked polyacrylamide is 0.5%～1%.
9. transdermal drug combination preparation according to claim 1; Wherein, The condition of said contact comprises that the consumption of cross-linking agent is 0.5～1 mole of % of acrylamide monomer and cross-linking agent sum total amount, and the consumption of said initiator is acrylamide monomer and cross-linking agent sum total amount 0.5～1 mole ‰, and the weight ratio of said first solvent and acrylamide monomer and cross-linking agent sum total amount is 3～5: 1; The temperature of contact is 55～65 ℃, and the time of contact is 24～36 hours.
10. according to claim 1 or 9 described transdermal drug combination preparations; Wherein, Said cross-linking agent is selected from methylene diacrylamide, piperazine bisacrylamide, N, N '-dihydroxy ethyl bisacrylamide, N, at least a in the group that N '-the ethylene bisacrylamide is formed;
Said initiator is selected from least a in the group that azodiisobutyronitrile, ABVN, benzoyl peroxide, dibenzoyl peroxide, the benzoyl peroxide tert-butyl ester, methyl ethyl ketone peroxide form;
Said first solvent is selected from least a in the group that acetone, butanone, methyl amylketone, methyl iso-butyl ketone (MIBK), Ketohexamethylene, methanol, ethanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol forms.
11. transdermal drug combination preparation according to claim 1 or 9; Wherein, Be added with the unsaturated carboxylic acid that carbon-carbon double bond has polymerization activity in said first solvent, the amount that the carbon-carbon double bond of interpolation has the unsaturated carboxylic acid of polymerization activity is 10～15 moles of % of acrylamide monomer and cross-linking agent sum total amount.
12. transdermal drug combination preparation according to claim 1; Wherein, After the method for said precipitation polymerization also is included in the precipitation polymerization completion, isolate the crosslinked polyacrylamide solid of contact gained, then with this crosslinked polyacrylamide solid of second organic solvent washing; Said second organic solvent does not dissolve crosslinked polyacrylamide solid, but can dissolve acrylamide monomer and cross-linking agent.
13. transdermal drug combination preparation according to claim 6, wherein, said active constituents of medicine is the water soluble drug that is used for transdermal administration.
14. according to claim 1 or 13 described transdermal drug combination preparations, wherein, said active constituents of medicine is pharmaceutical grade protein or the genomic medicine that is used for transdermal administration.
15. transdermal drug combination preparation according to claim 14, wherein, said pharmaceutical grade protein is polypeptide drugs.
16. a transdermal drug test kit is characterized in that, this test kit comprises any described transdermal drug combination preparation in microneedle array and the claim 1～15.
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| CN1072863A (en) * | 1991-10-16 | 1993-06-09 | 理查森-维克斯有限公司 | Be used to improve the dermal osmosis system of the reinforcement of medicine localized delivery |
| CN1883450A (en) * | 2005-06-23 | 2006-12-27 | 广州市拜澳生物科技有限公司 | A hydrophilic gel plaster substrate |
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| CN1072863A (en) * | 1991-10-16 | 1993-06-09 | 理查森-维克斯有限公司 | Be used to improve the dermal osmosis system of the reinforcement of medicine localized delivery |
| CN1883450A (en) * | 2005-06-23 | 2006-12-27 | 广州市拜澳生物科技有限公司 | A hydrophilic gel plaster substrate |
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