CN1470234A - Capsaicin liposome preparation for skin - Google Patents

Abstract

The invention refers to a capsaicin liposome preparation for local use, applied to cure neuralgia caused by the zona, diabetic neuralgia, psoriasis, skin pruritus and wound union. It can remarkably increase the content of the drug in the skin, reduce the thrill of capsaicin to the skin, and make the skin brighter. The preparing technique is simple, able to make industrialized production.

Description

Capsaicin liposome preparation for skin

Technical field the present invention relates to the capsaicin liposome preparation that skin is used, and it is painful that said preparation is used for the treatment of the nerve that causes behind the herpes zoster, and diabetic is neural painful, psoriasis, diseases such as skin pruritus.

The background technology capsaicin is the pungent vanilloyl Alkaloid of a kind of extreme, the white plates crystallization, and fusing point is 65-66 ℃, can from natural capsicum, extract, biological cell cultivation and chemosynthesis (the Tianjin pharmacy, 1997,9 (2), 24-26).In recent years, it is clinical that capsaicin has been applied to department of dermatologry, external commodity mainly contain Zostrix (0.025%, Gen Derm, USA), Doublecap (0.05%, Breckenridge Pharmaceutical), Zostrix-HP (0.075%, Gen Derm, USA) Dolorac (0.25%, Gen Derm, USA), the treatment dermatosis is very effective.

Capsaicin can make P material in the local nerve tip (substance P) exhaust to the therapeutical effect of dermatosis and it, and stops its accumulative again effect relevant.The P material be a kind of from outside thoughtful central nervous system transmit the main chemical mediator that pain impulsion and some gargalesthesia are felt, the middle release of replying at the destructive stimulus in the external world, cause hyperesthesia, and capsaicin is the antagonist of first P material, it can make P material in the sensory nerve on every side reduce and organize it to put aside again, thus make skin to pain or itch insensitive.The P material still is that a kind of important inflammatory mediator and strong blood vessel expand agent, it is included among the As and C nerve fiber of skin, and therefrom discharge, intradermal injection can cause skin erythema, edema and pruritus, it can cause that also various inflammatory mediators comprise histamine, the release of kassinin kinin and prostaglandin or additional, and the expansion that capsaicin can suppress the local skin blood vessel effectively as the antagonism and the depletor of P material, the medium and small P material that imports in sensory nerve ending and the vertebra gelatinoid of skin is discharged, thereby treatment scytitis, psoriasis, dermatosis such as skin pruritus (clinical department of dermatologry magazine, 1993,6,320-322).

Watson (Chinese Journal of New Drugs, 1994,3 (4) 10-13) etc. makes 0.025% emulsifiable paste with capsaicin, and neuropath behind 33 herpes zoster has been carried out 4 months treatment, applies every day 4 times, and total effective rate is 78% after 4 weeks; (J Am Acad Dermatol, 1987,17 (1): 93) neuropath uses the emulsifiable paste that contains capsaicin 0.025% to carry out the treatment of 4 weeks to Bernstein etc. behind the herpes zoster that 14 examples seriously are difficult to more than 60 years old cure, and total effective rate is 75%.

(Clin Ther such as Deal, 1991,13:383) select 101 patients to carry out the control experiment of double blinding excipient, with 0.025% capsaicin emulsifiable paste 4 week treatment, patient's pain of suffering from rheumatic arthritis obviously alleviates and reaches 33%, and what rheumatoid arthritis pain obviously alleviated is 57%.

Select 227 examples to carry out double blinding excipient comparative study experiment with nerve mild or moderate diabetics, carry out the treatment of 8 weeks with the ZHITONG GAO that contains capsaicin 0.075%, patient above 70% keenly feels and obviously alleviates, adopt the treatment of 0.025%% capsaicin emulsifiable paste once to use the invalid diabetic neuralgia patient of multiple Drug therapy, affected part coating three times on the one, pain complete obiteration (Tianjin pharmacy, 1997 after five days, 9 (2), 24-26).

The onset of psoriasis area is accounted for the gross area more than 10%, and average course of disease 34 routine patients in 19.2 carry out six week treatments, the state of an illness all alleviate 67.5%, erythema alleviate 59%, the silver bits peel off 70.6%.To the psoriatic of 197 examples with pain, external capsaicin and excipient carry out the double blind control experiment, totally 6 weeks, capsaicin treatment group has patient's skin lesion of 82% to disappear or significantly improves, and vehicle group is 33%, and the capsaicin frost is to lichen chronicus simplex (comprising the nodositas pruritus), burn back pruritus and blood ooze out relevant pruritus certain itching-relieving action (Tianjin pharmacy, 1997,9 (2), 24-26).

Capsaicin also is used to prevent cancer, aspects such as fat-reducing (external medicine: plant amedica fascicle, 1997,12 (2): 61-65).

In sum, capsaicin is painful to treating the nerve that causes behind the herpes zoster, and diabetic is neural painful, psoriasis, and dermatosis such as skin pruritus have significant curative effect, can also prevent cancer, help fat-reducing.External at present existing four kinds of capsaicin external preparation Zostrix, Doublecap, Zostrix-HP and Dolorac, domestic existing capsaicin ointment enters clinical experiment.

Because the action time of capsaicin is very short, capsaicin frost and ointment used 3-5 time in one day, and access times are more, and compliance of patients is poor; And side effect is bigger, and the agents area patient has burn feeling, twinge, and pruritus and erubescence have many patient Yin Nai to can't stand its side effect and abandoning cure, have therefore limited the popularization of the clinical practice of capsaicin.

Summary of the invention the purpose of this invention is to provide that a kind of access times are few, and toxic and side effects is little, patient's adaptable skin Liposomal formulation.

Solution of the present invention be based on skin with Liposomal formulation advantage:

Can wrap up hydrophilic preferably or lipophilic medicament, the carrier as insoluble drug has solubilization to medicine

The lipid physical ability increases the interior effect of lipoid that medicine enters horny layer or epidermis, increases medicine tiring out at local skin

Long-pending, thus play lasting drug release effect

Liposome has the effect of the speed limit envelope barrier of medicine whole body absorption, and the whole body that reduces medicine absorbs, and avoids medicine

Toxic and side effects, thereby reach its skin targeting

The composition of liposome such as phospholipid and skin lipid have high similarity, and biodegradable, not only skin are not had

Zest also has the effect of skin moistening

Medicine of the present invention has following component to make: (consumption is weight percentage)

Capsaicin 0.001%～20% phosphatidase 10 .01%～20%

Cholesterol 0.01%～10% ethanol 0.01%～20%

The buffer surplus

The preferred percentage by weight of the prescription of preparation medicine of the present invention is:

Capsaicin 0.010～10% phosphatidase 10 .01%～10%

Cholesterol 0.1%～5% ethanol 0.01%～10%

The buffer surplus

Optimum weight percentage ratio of the present invention is:

Capsaicin 0.25% phosphatidase 15 %

Cholesterol 2.5% ethanol 5%

The buffer surplus

Above-mentioned each component is made medicine production method of the present invention is:

Get an amount of capsaicin, phospholipid, cholesterol, it is dissolved in 50 ℃～70 ℃ the ethanol, alcoholic solution is joined in the synthermal buffer of certain volume, stir rapidly simultaneously.Fully behind the mixing, be cooled to room temperature rapidly and get final product; Also can add additives and be prepared into cream, unguentum, lotion and gel etc.

The phospholipid that is adopted in the said method comprises the phospholipid that some are natural, for example soybean phospholipid and egg yolk lecithin etc.; Or some synthetic phospholipid, for example stearic acid or myristic acid or Palmic acid, they are different aspect the parameter of the fusing point of the number of carbon atom, chain length, aliphatic chain and decision liposome physicochemical property.

Cholesterol is used for regulating the stability and the drug release of liposome, can also be with having following composition and the compositions similar to skin prepares liposome: ceramide, cholesterol, sulphuric acid cholesterol and fatty acid.

Use for transdermal, unilamellar liposome has bigger advantage (because volume is less thereby permeability is better) than multilamellar liposome, and we can prepare unilamellar liposome with means such as ultrasonic.

An important feature of the present invention is to utilize local topical lipid physical ability to increase the interior effect of lipoid that medicine enters horny layer or epidermis, increase the accumulation of medicine at local skin, thereby play lasting drug release effect, can effectively reduce simultaneously the frequency of utilization of external preparation, make medication more convenient, more comfortable, compliance of patients is good.

Another important characteristic of the present invention is because ethanol to the skin nonirritant, and can also increase the permeability of medicine to skin, therefore need not vapor away ethanol after preparing liposome with alcohol injection.

Another important feature of the present invention is the effect that liposome has the speed limit envelope barrier of medicine whole body absorption, the whole body that reduces medicine absorbs, avoid the whole body toxic and side effects of medicine, its skin Targeting Performance is enough to be enriched in skin area with active drug molecule thereby reach.

Another important feature of the present invention is because medicine is encapsulated in liposome interior, significantly reduces the stimulation of medicine to skin

The liposome that another important feature of the present invention is to use comprises a certain amount of moisture in preparation process, contact with the phospholipid layer of skin surface is affine by liposome, can replenish the loss of moist of skin surface, to keeping skin appropriateness moisture, it is coarse to reduce skin surface, improve skin appearance, have the crease-resistant effect of tangible skin-protecting face nursing.Phospholipid has skin care effect in addition, with after can obviously improve skin.

Skin Liposomal formulation of the present invention, preparation technology is simple, and cost is lower, can be prepared into multiple exterior-applied formulation, as cream, unguentum, lotion and gel.

Skin of the present invention is mainly used in the nerve that causes behind the treatment herpes zoster with Liposomal formulation and aches, and diabetic is neural painful, psoriasis, dermatosis such as skin pruritus and wound healing.Concrete mode

The example of preparation method:

Capsicine 0.25g, phosphatidase 15 g, cholesterol 2.5g joins in 5ml65 ℃ the ethanol dissolving.The above-mentioned injection of solution of syringe holder of using 10ml then stirs rapidly in 95ml65 ℃ buffer solution simultaneously.Injected the back and stirred 30min, be cooled to room temperature rapidly and get final product.Pharmacokinetic study:

Do contrast with the capsaicin emulsifiable paste that contains same concentrations, studied capsaicin liposome pharmacokinetics in vivo.

With rat back skin unhairing 3 * 3cm. dosage is 0.5g, 2 times on the one, and medication 3 days, medication 1.5,6 the last time, and after 12,18,24 hours, the sacrificed by decapitation rat peels off skin and subcutaneous tissue rapidly, blood sample collection.Skin was placed on 60 ℃ the glass plate heating 1 minute, and separated epidermis and corium, measure the content of capsaicin in epidermis, corium, subcutaneous tissue and the blood sample with the two sides cutter.

The table one medication influence that capsaicin liposome disposes medicine after 72 hours

Epidermis (μ g/mg) corium (μ g/mg) subcutaneous tissue (μ g/mg) blood (μ g/ml) sample time

Liposome ointment liposome ointment liposome ointment liposome ointment

2960.1± 556.7± 165.3± 80.7± 75.5± 39.2± 0.820± 0.102±1.5

753.1 236.7 56.8 36.8 56.4 12.6 0.052 0.023

1854.7± 485.2± 128.6± 37.6± 45.3± 0.320± 0.042±6 28.3±9.8

503.6 268.9 38.6 16.8 28.9 0.032 0.008

1749.2± 350.6± 55.3± 29.4± 21.6± 0.178±12 15.6±5.3 -×

602.3 165.3 26.5 18.7 12.3 0.023

1538.9± 300.4± 0.08±24

9.6±5.6 4.5±2.5 2.3±1.5?1.7±0.8 -×

456.8 142.8 0.005

Annotate: each data is that the meansigma methods ± absolute standard of five samples is poor: detected less than medicine in the-expression blood: the concentration of medicine in epidermis, corium and subcutaneous tissue is the weight (mg) of weight (μ the g)/epidermis (corium and subcutaneous tissue) of medicine, and the concentration of medicine in blood is the volume (ml) of weight (μ the g)/blood of medicine

Liposome significantly increases the content of capsaicin in epidermis, corium, subcutaneous tissue and the blood as can be seen from the above table, increase the holdup time of medicine at epidermis, corium, subcutaneous tissue and blood, help medicine and better bring into play curative effect, reduce the medication number of times, increase compliance of patients.It is reported that the analgesic activity of the capsaicin of high concentration significantly strengthens, skin can increase the drug level of medicine in skin with Liposomal formulation, helps the reinforcement of analgesic activity.The irritating research of preparation

Do contrast with the capsaicin emulsifiable paste that contains same concentrations, studied the skin irritation of capsaicin liposome.

Get four of adult rabbit (2KG), preceding 24 hours of medication is surveyed unhairing 3 * 4cm with animal spinal column two, check that skin is whether injured because of unhairing, unhairing district, left side is coated with liposome 1g, the right capsaicin ointment 1g that is coated with same concentrations that surveys, the extent of reaction of animal behind the observation coating, coating was twice on 1st, applied seven days, observe during the medication and after the medication agents area whether situations such as erythema and redness are arranged.

As can be seen from Table II, capsaicin liposome preparation can significantly lower the zest of capsaicin to rabbit skin, improves the state of skin, makes more brilliance of skin.

The degree of roughness rabbit fat plastid ointment liposome ointment liposome ointment liposome ointment 1 that the rabbit skin of table two capsaicin liposome is irritating investigates the red and swollen skin of reaction erythema of rabbit behind family's coating does not have to struggle and does not have serious no moderate brilliance coarse 2 and do not have the slight obviously brilliance-coarse 3 of violent the no moderate of struggling and do not have the reluctantly visible moderate of struggling not have the obvious no serious brilliance of the moderate brilliance coarse 4 slight nothings of struggling coarse

Select six experiment volunteers, it is 0.25% capsaicin liposome that an arm is coated with concentration, and the another arm is coated with the ointment of same concentrations, and one day twice, application was 3 days continuously, relatively its skin irritation.

The irritating investigation of the human body skin of table three capsaicin liposome

The degree of roughness volunteer of burning sensation twinge erubescence skin

Liposome ointment liposome ointment liposome ointment liposome ointment 1-* * * *-* * * * * * *-* * * 2-* * *-* *-* * *-* * * 3 * * * * * * * * * * * * * *-* * 4-* * * *-* * *-* * * *-* * 5-* * * *-* * *-* *-* 6-* * *-* *-* * *-* * *

Annotate: * * * * is very serious, and being impatient at the serious * * of * * * has manifest symptom * that light symptoms-asymptomatic is arranged

Wherein in the degree of roughness of skin-expression skin is than original brilliance more.

As can be seen from Table III, capsaicin liposome can significantly reduce the zest of capsaicin to human body skin, makes more brilliance of skin.

Claims (6)

1 one kinds of capsaicin liposome preparation for skin is characterized in that medicine has following components in weight percentage to make:

Capsaicin 0.001%～20% phosphatidase 10 .01%～20%

Cholesterol 0.01%～10% ethanol 0.01%～20%

The buffer surplus

2 capsaicin liposome preparation for skin according to claim 1 is characterized in that each weight percentages of components is:

Capsaicin 0.010%～10% phosphatidase 10 .01%～10%

Cholesterol 0.1%～5% ethanol 0.01%～10%

The buffer surplus

3 capsaicin liposome preparation for skin according to claim 1 is characterized in that each weight percentages of components is:

Capsaicin 0.25% phosphatidase 15 %

Cholesterol 2.5% ethanol 5%

The buffer surplus

4 according to the described capsaicin liposome preparation for skin of claim 1, it is characterized in that described external preparation prepares with alcohol injection, and technology is simple, can suitability for industrialized production.

5 according to the described capsaicin liposome preparation for skin of claim 1, it is characterized in that described external preparation can be used as the water in the prescription, is prepared into cream, or unguentum, or lotion and gel.

6 according to the described capsaicin liposome preparation for skin of claim 1, and it is painful to it is characterized in that described external preparation can be used for the treatment of the nerve that causes behind the herpes zoster, and diabetic is neural painful, psoriasis, dermatosis such as skin pruritus and wound healing.