CN102018655A - Transdermal medicament delivery combined preparation - Google Patents
Transdermal medicament delivery combined preparation Download PDFInfo
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- CN102018655A CN102018655A CN2009100925529A CN200910092552A CN102018655A CN 102018655 A CN102018655 A CN 102018655A CN 2009100925529 A CN2009100925529 A CN 2009100925529A CN 200910092552 A CN200910092552 A CN 200910092552A CN 102018655 A CN102018655 A CN 102018655A
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- Prior art keywords
- carnitine
- gel
- preparation
- weight
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- Prior art date
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Images
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a transdermal medicament delivery combined preparation. The transdermal medicament delivery combined preparation comprises a micro needle array and a gel preparation, wherein the gel preparation contains L-carnitine and/or derivative thereof. The transdermal medicament delivery combined preparation enables a large amount of L-carnitine to enter the body, can keep relatively stable L-carnitine concentration in the blood, and prolongs the distribution time of medicaments in tissues so as to solve the problem that the L-carnitine injection is difficulty accumulated in the tissues. On the other hand, the micro needle assisting L-carnitine transdermal medicament delivery path avoids the speed limit process of oral administration as the intestinal tracts absorb the L-carnitine, so the bioavailability of the preparation is obviously higher than that of oral administration. Compared with other transdermal medicament delivery preparations, the transdermal osmosis quantity of the L-carnitine in the preparation is remarkably improved.
Description
Technical field
The present invention relates to a kind of transdermal administration combination preparation.
Background technology
L-carnitine claims carnitine again, DL-carnitine chloride, and chemical name is L-beta-hydroxy-gamma-trimethylamine butanoic acid, and is very easily water-soluble, is human essential nutrient substance, is a kind of chemical compound relevant with the body fat acid metabolic.L-carnitine is transported to long-chain fatty acid in the film as the form of carrier with fatty acyl carnitine outside mitochondrial membrane, play the function that promotes that fatty acid metabolism needs for tissue.Cardiovascular system diseases, diabetes, hepatopathy, nephropathy and muscular movement impaired patients are found in clinical research, all lack phenomenon with L-carnitine in the body.Human body itself has the ability of synthetic l-carnitine, but for old man and baby, generates the needed enzyme of L-carnitine owing to lack in the body, relatively is easy to generate the L-carnitine deficiency disease.Along with development of science and technology, physicians have carried out further research to the effect of L-carnitine and derivant thereof, find the various clinical effect of L-carnitine, as improve the heart damage that myocardial ischemia situation and heart rhythm disorders, minimizing myocardial infarction cause.In addition, L-carnitine also all has better curative effect to the diseases such as complication that fatty liver, nephropathy, hyperlipidemia and diabetes cause.The L-carnitine derivant also has important function, can treat diseases such as cardiovascular and cerebrovascular disease, hypomnesis, senile dementia.The L-carnitine or derivatives thereof is just causing great interest of people and concern.
At present, the pharmaceutical preparation that contains L-carnitine is generally dosage forms such as the tablet that is fit to oral administration, capsule, however since during oral administration medicine cause bioavailability of medicament to reduce at gastrointestinal degraded and liver first-pass effect, and having undulatory property, only is 3-15%.Another common dosage form is the injection that is suitable for intravenous administration.Though intravenous injection is effective, injection point causes local skin damage, hemorrhage easily, simultaneously, the drug metabolism excessive velocities, it is of short duration to cause reaching effective drug duration.Therefore be not suitable for the treatment of long-term and chronic disease.Therefore, traditional oral administration and intravenous administering mode all are not the ideal administering modes of L-carnitine or derivatives thereof.
A kind of novel route of administration is a transdermal administration.The transdermal administration technology can make medicine pass through skin with constant relatively speed, absorbs through blood capillary to enter the body circulation, plays whole body and local therapeutic effects.But keratodermatitis makes the strong medicine of hydrophilic be difficult to pass through skin and enters in the body as the natural cover for defense of human body.Therefore, medicine is entered intravital obstacle, promote drug permeability, need in conjunction with the short technology of oozing of effective percutaneous in order to overcome human body skin.At present, the Chang Yong short technology of oozing has chemical penetrating agent, electroporation, iontophoresis, micropin and ultrasonic.Behind the micropin drug-supplying system effect skin that wherein has certain array, stay small hydrophilic duct, micromolecular medicine can enter with higher infiltration rate and produce therapeutical effect in the body, and can not stay skin trauma.But the especially effectively Percutaneously administrable preparation that also is not suitable for L-carnitine at present.
Summary of the invention
The objective of the invention is to overcome the shortcoming that present L-carnitine pharmaceutical preparation administering mode exists, a kind of transdermal administration combination preparation that is suitable for L-carnitine and/or its derivant transdermal administration is provided, thereby a large amount of L-carnitines and/or its derivant slowly and effectively are discharged in the body for a long time.
The mode that the objective of the invention is to use the auxiliary transdermal administration of micropin increases the bioavailability of L-carnitine and medicine at the content of respectively organizing in the internal organs, and a kind of L-carnitine combination preparation that is better than traditional oral administration and intravenous administration mode is provided.
The invention provides a kind of transdermal administration combination preparation, wherein, this transdermal administration combination preparation comprises microneedle array and gel preparation, contains L-carnitine and/or its derivant in this gel preparation.
According to one embodiment of the present invention, in the transdermal administration combination preparation of the present invention, the cross sectional shape of described micropin is conical or polyhedral cone shaped, and the height of micropin is between the 50-400 micron, the needle point diameter is between 100 nanometers-10 micron, and the cone angle of micropin maximum cross-section is the 30-60 degree.
According to another embodiment of the invention, in the transdermal administration combination preparation of the present invention, the total content of described L-carnitine and/or its derivant is the 0.1-55 weight % of described gel preparation gross weight.The medicine that described L-carnitine derivant is selected from L-carnitine can be accepted at least a in the group that acceptable salt that the medicine of the drug acceptable salt of acylate, L-carnitine and L-carnitine can accept acylate etc. formed.Further preferred described L-carnitine derivant is selected from acetyl-L-carnitine, propionyl levo-carnitine, L-carnitine hydrochloride, L-carnitine-L-tartrate, Carnitine Fumarate, the L-carnitine Orotate, the L-carnitine citrate, the L-carnitine glutamate, Glu, the L-carnitine palmitate, the L-carnitine malate, the acetyl-L-carnitine hydrochlorate, the propionyl levo-carnitine hydrochlorate, the glutaryl L-carnitine hydrochloride, at least a in the group that fumaroyl L-carnitine hydrochloride and glutamy L-carnitine hydrochloride etc. are formed.
According to another embodiment of the invention, in the transdermal administration combination preparation of the present invention, described gel preparation is external preparation for skin ointment or external preparation for skin paster.When described gel preparation is external preparation for skin ointment, this external preparation for skin ointment comprises gel-in-matrix and the L-carnitine and/or its derivant that are dispersed in this gel-in-matrix, and described gel-in-matrix contains water, biocompatibility macromolecule copolymer, wetting agent and antiseptic.Wherein, gross weight with this gel-in-matrix is a benchmark, content at biocompatibility macromolecule copolymer described in this gel-in-matrix is 0.01-10 weight %, the content of described wetting agent is 0.01-10 weight %, the content of described antiseptic is 0.01-5 weight %, and the content of described water is 75-99.97 weight %.
When described gel preparation is when having the external preparation for skin paster of self adhesion, this external preparation for skin paster comprises gel paster matrix and the L-carnitine and/or its derivant that are dispersed in this gel paster matrix, and described gel paster matrix contains water, biocompatibility macromolecule copolymer, binder, wetting agent and antiseptic.Wherein, gross weight with this gel paster matrix is a benchmark, content at biocompatibility macromolecule copolymer described in this gel paster matrix is 0.5-30 weight %, the content of described binder is 0.01-15 weight %, the content of described wetting agent is 0.01-10 weight %, the content of described antiseptic is 0.01-5 weight %, and the content of described water is 40-99.47 weight %.
The present invention is by making gel preparation with L-carnitine, and with this gel preparation and microneedle array mating reaction, thereby obtain transdermal administration combination preparation of the present invention.By this transdermal administration combination preparation is used for transdermal administration, compare with intravenous injection, microneedle array effect skin does not have pain, can not stay infection point, during administration, can keep constant effective blood drug level, and medicine continuous action time in each tissue is longer, the shortcoming of avoiding intravenous injection onset time weak point and being difficult in enrichment in the tissue; Compare with oral formulations, the gel preparation that the present invention uses does not have the peak valley phenomenon of oral formulations by skin absorbs, and has avoided small intestinal for the rate-limiting step that L-carnitine absorbs, and has improved bioavailability of medicament.The pharmaceutical dosage form that is suitable for the L-carnitine or derivatives thereof of transdermal administration provided by the invention, for simple, convenient and treat and/or prevent effectively that some chronicity diseases and chronic disease provide may.
In addition, of particular note, conventional transdermal administration medicine in conjunction with microneedle array, the medicine total amount that enters body-internal-circulation every day generally is lower than tens milligrams.Yet the present inventor but finds, adopt transdermal drug combination preparation of the present invention, only need the infiltration capacity of 6 hours L-carnitines and/or its derivant but can reach the 200mg/ Mus, and the bioavailability of this L-carnitine and/or its derivant also can reach 81.7%, this shows, the present invention utilizes the transdermal administration mode to realize making a large amount of L-carnitines to enter in the body and keeps in the blood L-carnitine concentration relatively stably, can reach the purpose that improves bioavailability and prolong drug effect.Compare with other Percutaneously administrable preparation, the transdermal penetration amount of the L-carnitine among the present invention has been significantly increased, has widened the drug dose scope that is applicable to percutaneous dosing and can realize very excellent drug effect, and therefore transdermal administration combination preparation of the present invention is particularly suitable for the transdermal administration of L-carnitine.
The experimental result of embodiment shows that transdermal administration combination preparation of the present invention has higher transdermal penetration.The rat in vivo test is the result show, in medication 6 hours, L-carnitine enters the intravital medication amount of rat can reach the 200mg/ Mus, and does not all have to realize so a large amount of transdermal penetration amount for traditional transdermal administration approach and the short transdermal administration approach that oozes of micropin.With traditional administering mode comparatively speaking, the auxiliary L-carnitine transdermal administration approach of micropin provides a kind of to be continued, metastable blood drug level, prolonged the distribution time of medicine in tissue, thereby solved the problem that the L-carnitine drug administration by injection is difficult to accumulate in tissue.The auxiliary L-carnitine transdermal administration approach of micropin has avoided oral administration because of the speed limit process of intestinal to the L-carnitine absorption on the other hand, so its bioavailability is apparently higher than oral administration.The present invention verifies that by the pharmacodynamic experiment of multiple dosing L-carnitine gel preparation of the present invention has the effect of blood fat reducing after the auxiliary administration of micropin.
Description of drawings
Fig. 1 is a micropin maximum cross section cone angle sketch map.
Fig. 2 is the skin of microneedle array after handling, the curve chart of L-carnitine and/or its derivant transdermal penetration.
Fig. 3 is rat injection, the oral and interior blood drug level time history plot of the auxiliary L-carnitine body of micropin.
Fig. 4 is the curve chart of different tissues Chinese medicine concentration changes with time in the rat body.
Fig. 5 is the sketch map of L-carnitine concentration relationship in interior triglyceride reduction amount of rat body and the gel preparation.
The specific embodiment
The invention provides a kind of transdermal administration combination preparation, this transdermal administration combination preparation comprises microneedle array and gel preparation, contains L-carnitine and/or its derivant in this gel preparation.
Under the preferable case, the pH value of described gel preparation is 5-7.5.In above-mentioned pH value scope, the storage stability of described gel preparation is good.The pH value of described gel preparation can pass through alkaline matter, as a kind of adjusting the in NaOH, the triethanolamine.
The content of L-carnitine and/or its derivant can change in a big way in the described gel preparation, but under the preferable case, the total content that contains L-carnitine and/or its derivant in the described gel preparation is the 0.1-55 weight % of gel preparation gross weight, more preferably 5-50 weight %.When the L-carnitine total content was lower than 5 weight % in every gram gel preparation, it was on the low side to enter intravital drug level, can play local drug effect, is difficult to reach the therapeutic purposes that are applied to systemic circulation.When the L-carnitine total content is higher than 50 weight % in every gram gel preparation, enter intravital medication amount and can not be significantly improved, simultaneously, the too high meeting of drug loading has influence on the mode of appearance of preparation in the preparation.In above-mentioned preferred content range, medicine can enter systemic circulation performance drug effect, and the mode of appearance of preparation is relatively good.
The medicine that the medicine that described L-carnitine derivant can be a L-carnitine can be accepted the drug acceptable salt of acylate, L-carnitine and L-carnitine can be accepted one or more in the acceptable salt of acylate.Under the preferable case, described L-carnitine derivant is an acetyl-L-carnitine, propionyl levo-carnitine, L-carnitine hydrochloride, L-carnitine-L-tartrate, Carnitine Fumarate, the L-carnitine Orotate, the L-carnitine citrate, the L-carnitine glutamate, Glu, the L-carnitine palmitate, the L-carnitine malate, the acetyl-L-carnitine hydrochlorate, the propionyl levo-carnitine hydrochlorate, the glutaryl L-carnitine hydrochloride, in fumaroyl L-carnitine hydrochloride and the glutamy L-carnitine hydrochloride one or more, these L-carnitine derivants have physicochemical properties more similar to L-carnitine and medical functions.The research report is arranged, L-carnitine, acetyl-L-carnitine and propionyl levo-carnitine are used in combination, male infertility for the more weak class of motility of sperm has reasonable curative effect, can be one or more mixture for the active ingredient in the preparation of the present invention therefore.
The structural formula of L-carnitine or derivatives thereof is as follows:
In the transdermal administration combination preparation of the present invention, above-mentioned L-carnitine and/or its derivant are the active component in the described gel preparation.Except above-mentioned active component, described gel preparation also contains other and is used for the auxiliary gel-in-matrix that forms gel preparation.Described gel-in-matrix is for being the main water-soluable gel matrix that is prepared from the water-soluble high-molecular material, and the water-soluable gel matrix has the advantages that drug loading is big and plasticity is good, not only principal agent is not had influence, and to the non-stimulated no irritated phenomenon of skin.Gel preparation provided by the invention can use with the dosage form of various transdermal administrations, and for different form of medication, the matrix of gel preparation may be different.For example, when described gel preparation was external preparation for skin ointment, described gel-in-matrix contained water, biocompatibility macromolecule copolymer, wetting agent and antiseptic.Wherein the gross weight with this gel-in-matrix is a benchmark, is preferably 0.01-10 weight % at the content of biocompatibility macromolecule copolymer described in this gel-in-matrix, and the content of described water is preferably 75-99.97 weight %.Further under the preferable case, being benchmark with the gross weight of this gel-in-matrix, is 0.01-5 weight % at the content of biocompatibility macromolecule copolymer described in this gel-in-matrix, and the content of described water is 89-99.96 weight %.
In order to give the storage characteristics of this gel preparation excellence, described gel-in-matrix also contains antiseptic, is benchmark with the gross weight of this gel-in-matrix, can be 0.01-5 weight % at the content of antiseptic described in this gel-in-matrix, is preferably 0.01-1 weight %.
For the mode of appearance and the water content of giving this gel preparation excellence, described gel-in-matrix also contains wetting agent, is benchmark with the gross weight of this gel-in-matrix, and the content of wetting agent can be 0.01-10 weight % in this gel-in-matrix, is preferably 0.01-5 weight %.
When described gel preparation is when having the external preparation for skin paster of self adhesion, this external preparation for skin paster comprises gel paster matrix and the L-carnitine and/or its derivant that are dispersed in this gel paster matrix, described gel paster matrix contains water, the biocompatibility macromolecule copolymer, binder, wetting agent and antiseptic, wherein the gross weight with this gel-in-matrix is a benchmark, content at biocompatibility macromolecule copolymer described in this gel paster matrix is preferably 0.5-30 weight %, the content of described binder is preferably 0.01-15 weight %, and the content of described water is preferably 40-99.47 weight %.Further under the preferable case, gross weight with this gel paster matrix is a benchmark, content at biocompatibility macromolecule copolymer described in this gel paster matrix is 1-25 weight %, and the content of described binder is 0.01-10 weight %, and the content of described water is 49-weight 98.96%.
For the mode of appearance and the water content of giving this gel preparation excellence, described gel paster matrix also contains wetting agent, gross weight with this gel paster matrix is a benchmark, and the content of wetting agent can be 0.01-10 weight % in this gel paster matrix, is preferably 0.01-5 weight %.
In order to give better plastic property of this gel preparation and the antimicrobial effect of protection skin; reduce the adsorption of other composition for medicine; described gel paster matrix can also contain filler; with this gel paster matrix gross weight is benchmark; content at filler described in this gel paster matrix can be 0-15 weight %, is preferably 0.01-10 weight %.
In order to give the storage characteristics of this gel preparation excellence, described gel paster matrix also contains antiseptic, gross weight with this gel paster matrix is a benchmark, can be 0.01-5 weight % at the content of antiseptic described in this gel paster matrix, is preferably 0.01-1 weight %.
When described gel preparation is that this external preparation for skin paster can comprise supporter, also can not comprise supporter when having the external preparation for skin paster of self adhesion.When this external preparation for skin paster comprises supporter, on the surface of described gel preparation attached to supporter.During use, gel preparation and contact skin are got final product.The material of described supporter can be one or more in non-woven fabrics, poly-Methane Carboxylic Acid ester, polyvinyl alcohol, cellulose acetate, cotton and the flannel.The thickness of described supporter is generally the 0.1-2 millimeter, and the thickness of gel preparation can be the 0.2-5 millimeter, is preferably the 0.5-3 millimeter, more preferably the 1-2 millimeter.
Described biocompatibility macromolecule copolymer is one or more in the water soluble drug adjuvant that allows to use in pharmacopeia; Be preferably in carbomer, chitosan, methylcellulose, carboxymethyl cellulose, carboxyethyl cellulose, carboxy-propyl cellulose, chitin, glucosan and derivant thereof, beta-schardinger dextrin-, Poly-L-lactic acid, xanthan gum, gelatin, polyvinyl alcohol, the polyesteramide one or more, the weight average molecular weight of described biocompatibility macromolecule copolymer is preferably 0.5 * 10
4-5 * 10
6, more preferably 1 * 10
4-1 * 10
6, further be preferably 5 * 10
4-5 * 10
5
Described binder can be various reagent with adhesive function, for example, in polyvidone, sodium carboxymethyl cellulose, sodium hydroxyethlcellulose, sodium carboxymethylcellulose pyce, ethyl cellulose sodium, Carboxymethyl cellulose sodium, sodium hydroxyethyl cellulose, carboxylic propyl methocel sodium, xanthan gum, sodium polyacrylate, polyvinyl alcohol, polyisobutylene and the polyacrylic acid one or more be can be, polyvidone and/or sodium carboxymethyl cellulose are preferably.The weight average molecular weight of described polyvidone is preferably 1 * 10
4-1 * 10
6
Described filler can not react with principal agent for various, and drug release and Transdermal absorption are not had the filler of influence, for example can be in Kaolin, zinc oxide, the calcium carbonate one or more.Under the preferable case, the particle diameter of described filler is the 1-100 micron.Under above-mentioned optimum condition, particle diameter 1-50 micron.
Described wetting agent be for can be various reagent with moisture-keeping functions, for example, can be in glycerol, propylene glycol, butanediol, dipalmitoyl hydroxyproline, Polyethylene Glycol, the hyaluronic acid one or more.The weight average molecular weight of described Polyethylene Glycol is preferably 1 * 10
2-5 * 10
4, more preferably 2 * 10
2-2 * 10
4, further be preferably 5 * 10
2-5 * 10
3
Described antiseptic can be the various medicine antiseptical reagent that can be used in, for example, can be in EDTA disodium, EDTA dipotassium, sorbitol, xylitol, methyl hydroxybenzoate sodium salt, ethyl hydroxybenzoate sodium salt, propylparaben sodium salt, methyl hydroxybenzoate potassium salt, ethyl hydroxybenzoate potassium salt, the propylparaben potassium salt one or more.
The preparation method of above-mentioned gel preparation provided by the invention is simple, as long as can obtain gelinite, can be earlier the various compositions of gel-in-matrix be mixed with into gel-in-matrix, and then with gel-in-matrix and active component mix homogeneously; Also can be directly the various compositions and the active component mix homogeneously of gel-in-matrix be prepared into gel preparation.
The present invention is above-mentioned gel preparation and microneedle array mating reaction, thereby obtains transdermal administration combination preparation of the present invention.When using transdermal administration combination preparation of the present invention, use microneedle array to act on skin, on skin, produce micropore simultaneously, the micropore degree of depth is generally the 80-100 micron, can not produce under the prerequisite of the pain sensation, realizes the epiderm skin pore.Described gel preparation is applied to above-mentioned micropin pore district, and the L-carnitine or derivatives thereof in this gel preparation will pass through skin along the aquation duct of aperture, enter the body circulation.
Described micropin can be a various micropin of the prior art, and its cross sectional shape is conical or polyhedral cone shaped, and the micropin height can be between the 50-400 micron, and the needle point diameter can be between 100 nanometers-10 micron, and the cone angle of micropin maximum cross-section is the 30-60 degree.The cone angle of described micropin maximum cross-section is meant along the angle of the axial cross section of described micropin, θ angle as shown in Figure 1.The material of described micropin 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.Described silicon pin can be available from Suzhou Nasheng Microelectronics Co., Ltd, described rustless steel micropin, metal micro-needle, glass micropipette or can prepare according to disclosed method in the corresponding document (seeing the embodiment part) respectively with the integrated degradable micropin of macromolecular material.
Use during the transdermal administration combination preparation of the present invention administration, a large amount of L-carnitines with or/its derivant enters in the body by skin pore district with higher and relative constant infiltration rate, and then pass through the body loop distribution in each tissue, the characteristics that reach metastable blood drug level and bring into play local drug effect.
In addition, of particular note, conventional transdermal administration medicine in conjunction with microneedle array, the medicine that enters body-internal-circulation every day generally is lower than tens milligrams.Yet the present inventor but finds, adopt transdermal drug combination preparation of the present invention, only need the infiltration capacity of 6 hours L-carnitine/or derivatives thereofs but can reach the 200mg/ Mus, and the bioavailability of this L-carnitine and/or its derivant also can reach 81.7%, this shows that the present invention utilizes the transdermal administration mode to realize the purpose that improves the L-carnitine bioavailability and prolong drug effect.Compare with other conventional transdermal administration medicine, the transdermal penetration amount of the L-carnitine among the present invention is significantly increased, widened the dosage range of the medicine that is suitable for percutaneous dosing and can realize very excellent drug effect, therefore transdermal administration combination preparation of the present invention is particularly suitable for the transdermal administration of L-carnitine.
Transdermal administration combination preparation of the present invention can be used for the treatment of cardiomyopathy that constitutional or Secondary cases L-carnitine deficiency disease cause and the chronic heart failure that heart disease caused; Also can be used for blood fat reducing, improve effects such as human motion ability and fat-reducing; Kidney dialysis carntine deficiency be can also be used for the treatment of, anemia, hypotension, weak, arrhythmia and angina pectoris improved.
The using method of gel preparation that contains L-carnitine and/or its derivant among the present invention and preparation method thereof and transdermal administration combination preparation is described below by embodiment.
Embodiment 1-13 is used for illustrating that transdermal administration combination preparation of the present invention contains gel preparation of L-carnitine and/or its derivant and preparation method thereof, wherein embodiment 1-9 and 13 preparations is external preparation for skin ointment, and what embodiment 10-12 prepared is the external preparation for skin paster.
Embodiment 1
Take by weighing the carbomer 980 of 0.025g, add in the ultra-pure water of 4.86g, leave standstill 4h after be uniformly dispersed, add a small amount of triethanolamine and regulate pH value between the 6-8, add the glycerol of 0.1g, the methyl hydroxybenzoate of 0.01g, vortex vibration 20s obtains the hydrogel matrix.Take by weighing the 6.25g L-carnitine and join in the 5g hydrogel matrix, behind the ultrasonic mixing, obtain aqueogel, place in 4 ℃ of refrigerators standby as external preparation for skin ointment.Wherein the gross weight with hydrogel matrix (carbomer 980, glycerol, methyl hydroxybenzoate and water) is a benchmark, the content of carbomer 980 is 0.5 weight % in the hydrogel matrix, the content of glycerol is 2 weight %, and the content of methyl hydroxybenzoate is 0.2 weight %, and surplus is a ultra-pure water.
Embodiment 2-4
Method according to embodiment 1 prepares gel preparation, different is, the amount that adds L-carnitine in the 5g hydrogel matrix is respectively 900mg, 2200mg and 6250mg, obtains the gel preparation that L-carnitine content in the gel preparation is respectively 15 weight %, 30 weight % and 55 weight %.
Take by weighing the carbomer 971 of 1g, L-carnitine, 1g acetyl-L-carnitine and the 1g propionyl levo-carnitine of 2g, the propylene glycol of 1g, the ethyl hydroxybenzoate sodium salt of 0.48g, the EDTA disodium of 0.02g, join in the ultra-pure water of 7.5g, leave standstill 4h after be uniformly dispersed, add triethanolamine and regulate pH value between the 6-8.Ultrasonic 20s, stirring at room obtains plastic aqueogel as external preparation for skin ointment, places in 4 ℃ of refrigerators standby.Wherein, gross weight with hydrogel matrix (carbomer 971, propylene glycol, ethyl hydroxybenzoate sodium salt, EDTA disodium and ultra-pure water) is a benchmark, the content of ultra-pure water is 75 weight % in the hydrogel matrix, the content of carbomer 971 is 10 weight %, the content of propylene glycol is 10 weight %, the content of ethyl hydroxybenzoate sodium salt is 4.8 weight %, and the content of EDTA disodium is 0.2 weight %.
Take by weighing the chitosan of 0.24g, add the aqueous acetic acid (through 0.22 μ m filtering with microporous membrane degerming) of the 2 weight % of 5g, stirring at room, after being uniformly dispersed, the NaOH that slowly adds concentration and be 0.5M regulates pH value between the 6-8.Add 0.1g glycerol, 0.01g methyl hydroxybenzoate, 0.003g hyaluronic acid, behind the vortex vibration 20s, adding 5ml concentration is the acetyl-L-carnitine aqueous solution of 40mg/ml, after stirring at room is even, obtain gel preparation, place in 4 ℃ of refrigerators standby as external preparation for skin ointment.Wherein acetyl-L-carnitine content is the 19.3mg/g gel, gross weight with gel-in-matrix (water, chitosan, acetic acid, glycerol, methyl hydroxybenzoate and hyaluronic acid) is a benchmark, the content of chitosan is 2.3 weight % in the gel-in-matrix, glycerol content is 0.97 weight %, the content of acetic acid is 0.97 weight %, the content of methyl hydroxybenzoate is 0.1%, and hyaluronic acid contents is that 0.03 weight % surplus is a water.
Embodiment 7
Take by weighing the Acritamer 940 of 0.01g, adding 99.97ml concentration is the aqueous solution of the L-carnitine-L-tartrate of 100mg/ml, leaves standstill 4h after be uniformly dispersed, and the NaOH that adds a little 1M regulates pH value between the 6-8, vortex vibration 20s.Add hyaluronic acid, the propylparaben sodium salt of 0.01g, the stirring at room of 0.01g, behind the mixing, obtain aqueogel, place in 4 ℃ of refrigerators standby as external preparation for skin ointment.Wherein the content of L-carnitine-L-tartrate is the 100mg/g gel, gross weight with gel-in-matrix (water, Acritamer 940, hyaluronic acid and propylparaben sodium salt) is a benchmark, the content of Acritamer 940 is 0.01 weight % in the gel-in-matrix, the content of propylparaben sodium salt is 0.01 weight %, hyaluronic acid contents is 0.01 weight %, and surplus is a water.
The 0.2g methylcellulose is scattered in (80 ℃) in the ultrapure hot water of 20ml.Place refrigerator and cooled to hide and spend the night to form solution.The carbomer 934 of 0.08g is scattered in the 20ml ultra-pure water, and the NaOH solution that adds 1M is regulated pH value to 6.0-8.0.The hyaluronic acid of the EDTA-disodium of 0.003g, 0.003g is dissolved in 5ml to be contained in the aqueous solution of 1g Carnitine Fumarate.Methylated cellulose aqueous solution, carbomer 934 hydrogel and the aqueous solution that contains EDTA-disodium, hyaluronic acid and Carnitine Fumarate are mixed, stirring at room, vortex vibration 1min obtains the gel preparation as external preparation for skin ointment, places in 4 ℃ of refrigerators standby.Wherein the content of Carnitine Fumarate is the 22mg/g gel, gross weight with gel-in-matrix (water, methylcellulose, carbomer 934, EDTA disodium and hyaluronic acid) is a benchmark, the content of methylcellulose is 0.4 weight % in the gel-in-matrix, the content of carbomer 934 is 0.2 weight %, the content of EDTA disodium is 0.006 weight %, hyaluronic acid concentration is 0.006 weight %, and surplus is a ultra-pure water.
Take by weighing the carbomer 980 of 0.05g, be dissolved in the ultra-pure water of 10ml, add the NaOH of a little 0.5M, to reduce carbomer 980 swelling times, the NaOH that fully adds 0.5M after the swelling again is to regulate between the pH to 6-8.Add 10mg acetyl-L-carnitine hydrochlorate, the 0.002g ethyl hydroxybenzoate behind the ultrasonic hydrotropy, obtains the gel preparation as external preparation for skin ointment, places in 4 ℃ of refrigerators standby.Wherein acetyl-L-carnitine hydrochlorate content is the 1mg/g gel, gross weight with gel-in-matrix (water, carbomer 980 and ethyl hydroxybenzoate) is a benchmark, the content of carbomer 980 is 0.50 weight % in the gel-in-matrix, and the content of ethyl hydroxybenzoate is 0.02 weight %, and surplus is a ultra-pure water.
With 3g carbomer 971,1.25g soluble metyl hydroxybenzoate salt is scattered in the 10ml ultra-pure water, adds triethanolamine and regulates pH value to 6, makes carbomer 971 hydrogels.Stirring at room.With the 12g gelatin, 1.25g methyl hydroxybenzoate and 7.5g polyvinylpyrrolidone K-30 (weight average molecular weight is 50000) join in the ultra-pure water of 10ml, and under 60 ℃ of conditions mix homogeneously, make composite gelatin solution; Behind above-mentioned 30.75g composite gelatin solution and above-mentioned 14.25g carbomer 971 hydrogel mix homogeneously, add 5g glycerol, make the gel paster matrix, add the 18g L-carnitine then, behind the mix homogeneously, coat on the non-woven fabrics, promptly get the external preparation for skin patch formulation.Wherein, gross weight with gel paster matrix (water, carbomer 971, methyl hydroxybenzoate, gelatin, polyvinylpyrrolidone K-30 and glycerol) is a benchmark, the content of carbomer 971 described in the gel paster matrix is 6 weight %, the content of methyl hydroxybenzoate is 5 weight %, the content of gelatin is 24 weight %, the content of polyvinylpyrrolidone K-30 is 15 weight %, and the content of glycerol is 10 weight %, and surplus is a ultra-pure water.
Embodiment 11
With 0.2g carbomer 980, the 0.005g methyl hydroxybenzoate is scattered in the 50ml ultra-pure water, adds triethanolamine and regulates pH value to 6, makes carbomer 980 hydrogels.Stirring at room.With the 0.3g gelatin, 0.005g methyl hydroxybenzoate and 0.01g polyvinylpyrrolidone K-30 (weight average molecular weight is 50000) join in the ultra-pure water of 49.47ml, and under 60 ℃ of conditions mix homogeneously, make composite gelatin solution; Behind above-mentioned 49.785g composite gelatin solution and above-mentioned 50.205g carbomer 980 hydrogel mix homogeneously, add 0.01g glycerol, make the gel paster matrix, add the 15g L-carnitine then, behind the mix homogeneously, coat on the non-woven fabrics, promptly get the external preparation for skin patch formulation.Wherein, gross weight with gel paster matrix (water, carbomer 980, methyl hydroxybenzoate, gelatin, polyvinylpyrrolidone K-30 and glycerol) is a benchmark, the content of carbomer 980 described in the gel paster matrix is 0.2 weight %, the content of methyl hydroxybenzoate is 0.01 weight %, the content of gelatin is 0.3 weight %, the content of polyvinylpyrrolidone K-30 is 0.01 weight %, and the content of glycerol is 0.01 weight %, and surplus is a ultra-pure water.
(weight average molecular weight is 1 * 10 with 1.5g gelatin, 1.2g polyvinyl alcohol
5) join 20ml and contain in the aqueous solution of 0.045g methyl hydroxybenzoate, mix homogeneously under 60 ℃ of conditions is made composite gelatin solution.(weight average molecular weight is 1 * 10 with the 1.2g sodium polyacrylate
7), (particle diameter is smaller or equal to 10 microns, Main Ingredients and Appearance SiO for 3g Kaolin
2Content is 53.7%, Al
2O
3Content be 44.97%) join in the 2.1g glycerol after mixing and stir, add above-mentioned composite gelatin solution then, stir under 60 ℃ of conditions and make the gel paster matrix, the L-carnitine that adds 1g then stirs, coat on the non-woven fabrics, promptly get the external preparation for skin patch formulation.Wherein the gross weight with gel paster matrix (gelatin, polyvinyl alcohol, methyl hydroxybenzoate, Kaolin, sodium polyacrylate and glycerol) is a benchmark, the content of gelatin is 5 weight % in the gel paster matrix, the content of polyvinyl alcohol is 4 weight %, the content of methyl hydroxybenzoate is 0.15 weight %, the content of sodium polyacrylate is 4 weight %, the content of glycerol is 7 weight %, and kaolinic content is 10 weight %, and surplus is a water.
Embodiment 13
The 3g L-carnitine joins in the hydrogel matrix that 97g embodiment 1 makes, and obtains the gel preparation that L-carnitine concentration is 3 weight %.
Comparative Examples 1
3g high molecular weight protein BSA (weight average molecular weight is 68000) is joined in the hydrogel matrix that 97g embodiment 1 makes, and obtaining high molecular weight protein BSA concentration is the gel preparation of 3 weight %.
Performance test
(1) transdermal penetration test: (specification of microneedle array is every square centimeter and contains 484 micropins to use the rustless steel microneedle array respectively, the micropin height is 300 μ m, the needle point diameter is 1 μ m, the taper angle theta of micropin maximum cross section is 45 degree, the distance of adjacent needle point is 800 μ m, according to W.Martanto in the document, S.P.Davis, N.R.Holiday, J.Wang, H.S.Gill, and M.R.Prausnitz, Transdermal Delivery of Insulin Using Microneedles in Vivo, Pharmaceutical Research, method preparation among 21 (2004) 947-952), (specification of microneedle array is every square centimeter and contains 484 micropins with the integrated solid silicon pin of silicon chip array, the micropin height is 150 μ m, the needle point diameter is 1 μ m, the taper angle theta of micropin maximum cross section is 45 degree, the distance of adjacent needle point is 800 μ m, Suzhou Nasheng Microelectronics Co., Ltd's product) and with the integrated degradable microneedle array of macromolecular material (specification of microneedle array is every square centimeter and contains 484 micropins, the micropin height is 400 μ m, the needle point diameter is 1 μ m, the taper angle theta of micropin maximum cross section is 45 degree, the distance of adjacent needle point is 800 μ m, according to document J.H.Parka, M.G.Allenb, M.R.Prausnitz Biodegradable polymer microneedles:Fabrication, mechanics and transdermal drug delivery, the method for introducing among Journal of Controlled Release 104 (2005) 51-66 preparation) to act on area respectively be 0.66cm to the micropin of three kinds of materials
2Skin 30s after, the aqueogel (local skin preparation) that the foregoing description 5-9 and 13 of 300mg is made is coated on the micropin site of action respectively, or the external preparation for skin paster of embodiment 10-12 is fixed in the micropin site of action; Use the upright jacket type diffusion cell of classical Franz, the specification of diffusion cell is: diffusion area is 0.66cm
2, the acceptable solution volume is 2.5ml, (unit is mg/cm to the accumulation infiltration capacity by calculating medicine in 8 hours
2) estimated the transdermal test in vitro permeability (method of high performance liquid chromatogram is measured L-carnitine and/or its derivatives concentration) of L-carnitine and/or its derivant.Test used skin material and be and use dermatome and plant from pig ear and get the skin that thickness is 800 μ m.
The result of L-carnitine and/or 8 hours accumulation infiltration capacity of its derivant transdermal is as shown in table 1, and wherein the L-carnitine of embodiment 5 and its derivant transdermal test in vitro permeability curve are also as shown in Figure 2.
Table 1
Can draw such conclusion from the result of table 1 and Fig. 2: use transdermal administration combination preparation of the present invention, under the auxiliary condition of microneedle array, the transdermal penetration of L-carnitine and/or its derivant is very high, and the micropin of three kinds of materials can reach the effect that promotes L-carnitine and/or its derivant transdermal penetration.
More as can be seen, under the situation of identical administration concentration and same micropin effect, micropin assists the infiltration capacity of L-carnitine gel preparation to be higher than the infiltration capacity of conventional model drug high molecular weight protein BSA gel preparation far away by embodiment 13 and Comparative Examples 1.
(2) the body giving drugs into nose is for dynamic experiment: selecting body weight is that the male SD rat of the health of 250 ± 20g is an experimental subject.Rat adapts to a week before the experiment, and all rats be can't help water in experiment fasting the previous day.Rat is divided into 3 groups, and every group comprises three rats in first group and second group.Comprise 23 rats in the 3rd group altogether, wherein three are used for testing blood Chinese medicine concentration, and other 20 are used for test organization Chinese medicine content.First group is the intravenous injection group, and dosage is the 200mg/ Mus, and injection is that concentration is the L-carnitine aqueous solution of 200mg/ml.Second group is the oral administration group, and dosage is the 200mg/ Mus, and oral agents is the L-carnitine aqueous solution of 200mg/ml.The 3rd group is the auxiliary transdermal administration group of micropin, and dosage is the 750mg/ Mus.First group of rat adopted the tail vein injection administering mode, respectively at 0min, and 3min, 6min, 10min, 20min, 30min, 1h, 2h, 4h, 8h and 12h gather the blood testing drug level; Second group of rat adopted and irritates appetite clothes administering mode, respectively at 0min, and 30min, 1h, 2h, 4h, 6h and 8h gather the blood testing drug level; The 3rd group of auxiliary transdermal administration group of micropin: (specification of microneedle array is every square centimeter and contains 484 micropins to select silicon pin array for use, the micropin height is 150 μ m, the needle point diameter is 1 micron, the taper angle theta of micropin maximum cross section is 45 degree, the distance of adjacent needle point is 800 μ m, Suzhou Nasheng Microelectronics Co., Ltd's product) acts on the 3rd group of rat skin 30s, skin active area 2cm
2, the aqueogel of embodiment 1 is made hydrogel patch be fixed in the micropin site of action, remove paster after 6 hours, and measure paster residual drug content.The blood sample acquisition time is respectively with the fixing back of paster 0h, 0.6h, 1h, 2h, 4h, 6h, 7h, 8h, 12h time point, gets the blood drug level of serologic test L-carnitine.Intravenous injection group, oral administration group and microneedle cutaneous group of plasma concentration curve are as shown in Figure 3.
The result shows, the auxiliary L-carnitine of micropin is actual, and to enter intravital medication amount be that (after off-test in the test body, the assay of the residue L-carnitine on the paster calculates the actual intravital medication amount that enters to the 200mg/ Mus.The result shows that actual to enter intravital medication amount be the 200mg/ Mus to the auxiliary L-carnitine of micropin), be higher than the drug osmotic amount of conventional transdermal administration far away.
In addition, the 3rd group rat is carried out the tissue sample collection, acquisition time is respectively 0h, 3h, 6h, 9h, 12h.The tissue sample of rat comprises heart, kidney, liver and chest muscle.Organize Chinese medicine content change curve such as Fig. 4 in time.
Wherein the L-carnitine concentration determination adopts classical enzyme process test kit in blood and the tissue, and test kit is available from (BIOTENSEC France), Cat.No.066.Table 2 has been concluded oral administration and microneedle cutaneous group of pharmacokinetic parameter.
Table 2
| C max | T max | AUC 0-∞(mg.h.mL -1) | F ab | |
| Oral | 54μg/ml | 2h | 0.269 | 8.40％ |
| The micropin transdermal | 462μg/ml | 4h | 2.573 | 81.70％ |
C
MaxBe the highest blood drug level; T
MaxFor reaching the pairing time of the highest blood drug level;
AUC
0-∞(mg.h.L
-1The expression lower area of blood concentration-time curve; F
AbThe expression absolute bioavailability.
Body giving drugs into nose shown in Fig. 3, Fig. 4 and the table 2 shows that for the dynamic test result behind the intravenous administration, the blood drug level of L-carnitine reduces very fast, and the blood drug level of 3min is 3.9mg/ml, and the blood drug level of 2h only is 271 μ g/ml.Behind the oral administration, blood drug level (C) is in low relatively scope, reaches the highest blood drug level (C
Max) time be 2h, C
Max54 μ g/ml, absolute bioavailability only are 8.40%.Behind the micropin transdermal, blood drug level remains on higher relatively scope, and relatively stable at 2h blood drug level during the 6h, C
2h=337 μ g/ml～C
6h=442 μ g/ml.Bioavailability reaches 81.70%.After administration finished, the very fast metabolism from blood of L-carnitine retained but still have in tissue.Therefore, use transdermal drug combination preparation of the present invention, under the auxiliary condition of micropin, make L-carnitine can enter body-internal-circulation in a large number, and it is relatively stable to keep haemoconcentration in a long time.Compare with oral administration, improved the bioavailability of L-carnitine greatly,, relatively large accumulating arranged in tissue because onset time is long.After this had also solved drug administration by injection, medicine was difficult in the drawback of accumulating in the tissue.
(3) pharmacodynamic experiment in the body: the selection body weight is that the male SD rat of the health of 170 ± 20g is an experimental subject.After feeding for 8 weeks by exogenous high lipid food, the content that detects the triglyceride of rat exceeds 8 to 10 times before raising, and body weight increases to 2 to 2.5 times before raising.(specification of microneedle array is every square centimeter and contains 484 micropins with the integrated solid microneedles array of silicon chip, the micropin height is 150 μ m, the needle point diameter is 1 μ m, the taper angle theta of micropin maximum cross section is 45 degree, the distance of adjacent needle point is 800 μ m, Suzhou Nasheng Microelectronics Co., Ltd produces) effect skin 30s, skin active area 2cm
2The aqueogel of embodiment 2-4 and the hydrogel matrix of embodiment 1 (promptly not containing L-carnitine) are administered into the above-mentioned pin position of executing respectively, do not contain the aqueogel Chinese medicine content that contains medicine among the hydrogel matrix of medicine and the embodiment 2-4 among the embodiment 1 and be followed successively by 0 weight % (zero-dose), 15 weight % (low dosage), 30 weight % (middle dosage) and 55 weight % (high dose).Execute the medicine hydrogel gross weight that contains on the pin position and be 1.2 grams, behind the successive administration 20 times, blood sampling is analyzed the changes of contents of triglyceride, and the result is plotted among Fig. 5.As can be seen from Figure 5, use transdermal administration combination preparation of the present invention after, the reduction amount of triglyceride all is higher than matched group.
Claims (10)
1. transdermal administration combination preparation, it is characterized in that: this transdermal administration combination preparation comprises microneedle array and gel preparation, contains L-carnitine and/or its derivant in this gel preparation.
2. transdermal administration combination preparation according to claim 1, wherein, the cross sectional shape of described micropin is conical or polyhedral cone shaped, and the height of micropin is between the 50-400 micron, the needle point diameter is between 100 nanometers-10 micron, and the cone angle of micropin maximum cross-section is the 30-60 degree.
3. transdermal administration combination preparation according to claim 1, wherein, the total content of described L-carnitine and/or its derivant is the 0.1-55 weight % of described gel preparation gross weight.
4. according to claim 1 or 3 described transdermal administration combination preparations; wherein, the described L-carnitine derivant medicine that the is selected from L-carnitine medicine that can accept the drug acceptable salt of acylate, L-carnitine and L-carnitine can be accepted at least a in the group that the acceptable salt of acylate forms.
5. according to claim 1 or 3 described transdermal administration combination preparations, wherein, described L-carnitine derivant is selected from acetyl-L-carnitine, propionyl levo-carnitine, L-carnitine hydrochloride, L-carnitine-L-tartrate, Carnitine Fumarate, the L-carnitine Orotate, the L-carnitine citrate, the L-carnitine glutamate, Glu, the L-carnitine palmitate, the L-carnitine malate, the acetyl-L-carnitine hydrochlorate, the propionyl levo-carnitine hydrochlorate, the glutaryl L-carnitine hydrochloride, at least a in the group that fumaroyl L-carnitine hydrochloride and glutamy L-carnitine hydrochloride are formed.
6. according to claim 1 or 3 described transdermal administration combination preparations, wherein, described gel preparation is external preparation for skin ointment or external preparation for skin paster.
7. transdermal administration combination preparation according to claim 6, wherein, described gel preparation is an external preparation for skin ointment, this external preparation for skin ointment comprises gel-in-matrix and the L-carnitine and/or its derivant that are dispersed in this gel-in-matrix, and described gel-in-matrix contains water, biocompatibility macromolecule copolymer, wetting agent and antiseptic.
8. transdermal administration combination preparation according to claim 7, wherein, gross weight with described gel-in-matrix is a benchmark, content at biocompatibility macromolecule copolymer described in this gel-in-matrix is 0.01-10 weight %, the content of described wetting agent is 0.01-10 weight %, the content of described antiseptic is 0.01-5 weight %, and the content of described water is 75-99.97 weight %.
9. transdermal administration combination preparation according to claim 6, wherein, described gel preparation is the external preparation for skin paster with self adhesion, this external preparation for skin paster comprises gel paster matrix and the L-carnitine and/or its derivant that are dispersed in this gel paster matrix, and described gel paster matrix contains water, biocompatibility macromolecule copolymer, binder, wetting agent and antiseptic.
10. transdermal administration combination preparation according to claim 9, wherein, gross weight with described gel paster matrix is a benchmark, content at biocompatibility macromolecule copolymer described in this gel paster matrix is 0.5-30 weight %, the content of described binder is 0.01-15 weight %, the content of described wetting agent is 0.01-10 weight %, and the content of described antiseptic is 0.01-5 weight %, and the content of described water is 40-99.47 weight %.
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