CN103610666A - Pramipexole dihydrochloride transdermal patch and preparation method thereof - Google Patents

Abstract

The invention specifically relates to a pramipexole hydrochloride transdermal patch and a preparation method thereof, belonging to the field of pharmaceutical preparations. The present invention uses a hydrophilic matrix mixed with a penetration enhancer and adopts a multi-layer patch technology to ensure that the drug is released at a constant rate for a long time and achieves a better penetration rate. The invention also discloses a preparation method thereof, which can be used to make a transparent patch with good uniformity.

Description

A kind of pramipexole hydrochloride transdermal patch and preparation method thereof

technical field

The invention relates to the field of pharmaceutical preparations, in particular to a transdermal patch of pramipexole hydrochloride and a preparation method thereof.

Background technique

Pramipexole is a non-ergot alkaloid dopamine agonist mainly used in the treatment of Parkinson's disease. It can be used alone to treat Parkinson's disease in the early stage, can delay the appearance of motor symptoms, and can improve the quality of life of patients compared with levodopa. In the late stage, it can be used in combination with dopamine to treat Parkinson's disease, which can reduce the dose of levodopa. Pramipexole has a neuroprotective effect on dopamine, and it has unique advantages in the treatment of neuroprotection and restless legs syndrome (RLS), which can significantly delay the development of Parkinson's disease. Compared with other ergot dopamine receptor agonists, it does not cause heart valve damage. In addition to treating motor symptoms in Parkinson's patients, pramipexole has also shown antidepressant effects. Pramipexole can be used as a first-line drug in Parkinson's patients with depression. However, the half-life of pramipexole hydrochloride is 8 to 12 hours, and it needs to be taken orally and needs to be administered repeatedly, which is easy to form a peak and valley phenomenon of blood concentration and cause side effects. Moreover, the vast majority of Parkinson's disease occurs in the elderly, and its oral administration regimen is complicated, and the dose needs to be increased every week to achieve an effective therapeutic dose, which makes the compliance of oral administration poor and prone to missed doses and wrong doses The phenomenon affects the treatment of patients. One-time administration of transdermal preparations can make the drug enter the body at a constant rate for a long time, similar to long-term intravenous injection, without oral administration, prolong the dosing interval, reduce the number of administrations and maintain a constant and effective blood drug concentration, thereby Improve patient compliance with medication and reduce adverse drug reactions.

Chinese patent CN102406626A discloses a sustained-release tablet of pramipexole hydrochloride, which can be released continuously and stably in the body for 24 hours without being affected by pH changes in the gastrointestinal tract environment, and needs to be taken once a day. However, this preparation has not been able to achieve long-acting slow release. Chinese patent CN102846541A discloses a pramipexole oral liquid. This oral dosage form can be used for patients with dysphagia in the middle and late stage of Parkinson's disease. It is convenient to take and improves the compliance of medication. However, multiple administrations are still required, which fails to make the medicine enter the body at a constant rate. Chinese patent CN1826113A discloses a transdermal drug delivery system containing pramipexole active agent, the drug in the polymer layer can release the active substance pramipexole stably and at a constant rate within 4-7 days. However, this transdermal delivery system was used for the free base form of pramipexole and was based on an area of 20 square centimeters. The administration area is relatively large, and the penetration rate is above 5ug/cm ² /h.

Contents of the invention

The object of the present invention is to provide a pramipexole hydrochloride transdermal patch and a preparation method thereof. This transdermal patch can maintain a constant rate of release of the drug for a long time, improve the compliance of patients with medication, and reduce the risk of side effects caused by the peak-valley phenomenon. The side effects that come make it safer and more effective. Secondly, increase the penetration rate of the drug and reduce the administration area. In addition, the present invention preferably adopts two-layer to multi-layer patch technology to ensure constant release of the drug over a long period of time. The drug-loading material used in the present invention is less, can be prepared into a thin transparent patch, has stable properties, is safe and non-irritating, and has good skin tolerance. The preparation method used in the invention has mild conditions, and the prepared drug patch has good uniformity. The drug in the patch has good skin permeability, and the patch with a small area can reach the effective therapeutic dose of the drug.

The present invention is realized by adopting the following scheme:

The transdermal patch of the present invention consists of a backing layer, a drug-containing layer and an anti-adhesive layer, and the drug-containing layer consists of the following components and weight ratios:

The above-mentioned drug-loading material is preferably selected from one or more of hydrophilic polymers and controlled-release film materials. The drug-loading material is more preferably a hydrophilic polymer.

The hydrophilic polymer is preferably one or more selected from polyvinyl alcohol, polyvinylpyrrolidone, polyacrylate or polyacrylamide, more preferably a mixture of polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP). The preferred model of PVA is 04-86, 04-88, 05-88 or 17-88, most preferably PVA17-88. The preferred model for PVP is K30. The preferred weight ratio of PVA to PVP is 15:1-1:20.

The release-controlling membrane material is preferably selected from microporous polypropylene or ethylene-vinyl acetate copolymer.

The above-mentioned penetration enhancer is preferably selected from Tween 80, eucalyptus oil, n-octanol, azone, azone, ethanol, menthol, dibutyl sebacate, oleic acid, dimethyl sulfoxide, glycerol, decane One or more of sodium sodium chloride, N-methylpyrrolidone or propylene glycol.

The plasticizer is preferably selected from one or both of glycerol, propylene glycol, sorbitol or polyethylene glycol. The stabilizer is preferably selected from one or both of disodium edetate, pyrosulfate, glutathione, vitamin C and vitamin E.

The drug-containing layer of the present invention is preferably 2 to 3 layers. More preferably 3 layers.

In the three-layer technical solution, the preferred solution is: the layer close to the anti-adhesive layer contains drug-loaded materials, penetration enhancers, plasticizers, stabilizers and drugs, wherein the drugs account for 10-30% of the total amount of drugs , based on 1 part of the drug contained in the three layers, the weight of the polymer in the layer is 20-120 parts, the weight of the penetration enhancer is 2-20 parts, the weight of the plasticizer is 1-30 parts, and the weight of the stabilizer is 1-30 parts . The middle layer does not contain drugs, but only contains drug-loaded materials, penetration enhancers and plasticizers, that is, the blank layer. The drugs contained in the three layers are used as 1 portion of juice, and the weight of the composition in this layer is 50-200 parts. The weight of the agent is 4-50 parts, and the weight of the plasticizer is 2-40 parts. One layer close to the backing layer contains drug-loaded materials, penetration enhancers, plasticizers, stabilizers and drugs, wherein the drugs contain 70-90% of the total amount of drugs, and the drug-loaded materials are preferably hydrophilic polymers, with three The drug contained in the layer is 1 part of juice, the weight of the composition in the layer is 30-180 parts, the weight of the penetration enhancer is 1-30 parts, the weight of the plasticizer is 2-40 parts, and the weight of the stabilizer is 2-50 parts.

In the three-layer technical scheme, another preferred scheme is: mix medicine, drug-loaded material, penetration enhancer and plasticizer to form three layers, and the medicine, drug-loaded material, penetration enhancer and plasticizer contained in the three layers The plasticizers are different, and the drug content ratio of the layer close to the anti-sticking layer, the middle layer and the layer close to the backing is 1:1.5:3～1:5:20.

The backing layer is composed of a single layer or film of polymer, or a composite film of multiple polymers and metal aluminum foil. The polymers can be polyvinyl chloride, high-density polyethylene, low-density polyethylene, polypropylene, polyolefins and polyesters. The best is low-density polyethylene film and metal aluminum foil made of polyethylene-aluminum-polyethylene composite film or polyurethane film.

The anti-adhesive layer can be composed of polyethylene, polystyrene, polypropylene, and a silicone release agent is used to avoid adhesion of pressure-sensitive adhesives.

The preparation method of the patch in the present invention: fully swell the hydrophilic polymer or viscous polymer with a solvent, add a penetration enhancer and a plasticizer to dissolve at a certain temperature, add a drug solution after the temperature drops, mix evenly, and cast a film. Dry and shape. For the multi-layer patch, prepare layer by layer, after drying and cooling, cover the backing layer and the anti-adhesive layer, and divide the preparation to complete.

The beneficial effects of the present invention are:

The invention can be used for the treatment of Parkinson's disease, and the permeation rate of the transdermal patch can reach more than 10ug/cm ² /h per day on average. In the treatment plan of ordinary tablets, a daily dose of 375ug is required in the first week, and a daily dose of 750ug is required in the second week when the dose is increased. 3.0mg, 4.5mg. According to the weekly dosing characteristics of pramipexole hydrochloride, the long-acting 84h patch only needs to be administered twice a week, and the corresponding dosing area can be increased every week to meet the treatment requirements. The size of the patch can be 2-2 24cm ² .

The experimental results of the present invention show that the pramipexole hydrochloride transdermal patch prepared by the hydrophilic polymer can achieve good long-term constant-rate release under the condition of joint use of a penetration enhancer, and the drug can reach a better penetration rate, An effective constant release rate is achieved on the first day of administration.

Description of drawings

Fig. 1 is the in vitro release and cumulative transdermal release of the patch of Example 1 within 84h

Figure 2 is the in vitro release and cumulative transdermal release of the patch of Example 2 within 84h

Fig. 3 is the in vitro release and cumulative transdermal release of the patch of Example 3 within 84h

Figure 4 is the in vitro release and cumulative transdermal release of the patch of Example 4 within 84h

Detailed ways

Example 1

The composition of the first layer (close to the release layer): 1.2g polyvinyl alcohol (PVA17-88), 0.3g polyvinylpyrrolidone (PVP), 0.2g eucalyptus oil, 0.12g azone, 800.2g Tween, Propylene glycol 0.4g, glycerin 0.2g, edetate disodium 0.1g, pramipexole hydrochloride 20mg.

The composition of the second layer (middle layer): polyvinyl alcohol (PVA17-88) 2.4g, polyvinylpyrrolidone (PVP) 0.6g, eucalyptus oil 0.4g, azone 0.24g, Tween 800.4g, propylene glycol 0.8g, glycerin 0.4g.

The composition of the third layer (close to the backing layer): polyvinyl alcohol (PVA17-88) 1.2g, polyvinylpyrrolidone (PVP) 0.3g, eucalyptus oil 0.2g, azone 0.12g, Tween 800.2g, propylene glycol 0.4 g, glycerin 0.2g, disodium 7-diamine tetraacetate 0.1g, pramipexole hydrochloride 60mg.

Preparation method: fully swell polyvinyl alcohol and polyvinyl pyrrolidone with 50% ethanol, add eucalyptus oil, Tween 80, azone, propylene glycol and glycerin, dissolve and mix with magnetic force at 70°C, and wait until the temperature drops to Add the drug aqueous solution at 40°C, mix well, let it stand until the bubbles disappear, lay the film by casting method, dry and form, and then compound after cooling, cover the polyethylene-aluminum-polyethylene composite film and polyethylene anti-adhesive layer, and divide the dose to prepare hydrochloric acid containing A transdermal patch of pramipexole 1.63mg/ ^cm2 .

A modified Franz diffusion cell was used to measure the permeability of the transdermal patch on the abdominal skin of the hair-free rats, and the area of the patch used in the transdermal diffusion experiment was 2.92cm ² . The permeation rate of pramipexole hydrochloride transdermal patch was 11.14ug/cm ² /h within 84 hours. The in vitro cumulative penetration curve is shown in Figure 1.

Example 2

The first layer (close to the anti-adhesive layer) composition: polyvinyl alcohol (PVA17-88) 2.0g, polyvinylpyrrolidone (PVP) 0.4g, N-methylpyrrolidone 0.2g, propylene glycol 0.3g, glycerin 0.3g, vitamin C0.2g, pramipexole hydrochloride 15mg.

The composition of the second layer (middle layer): polyvinyl alcohol (PVA17-88) 2.8g, polyvinylpyrrolidone (PVP) 0.2g, N-methylpyrrolidone 0.4g, propylene glycol 0.3g, glycerin 0.4g, vitamin C0.2g, hydrochloric acid Pramipexole 30mg.

The composition of the third layer (close to the backing layer): polyvinyl alcohol (PVA17-88) 1.4g, polyvinylpyrrolidone (PVP) 0.3g, N-methylpyrrolidone 0.2g, propylene glycol 0.2g, glycerin 0.2g, vitamin C0. 3g, pramipexole hydrochloride 45mg.

Prepared as in Example 1, prepared into a transdermal patch containing 1.84 mg/ ^cm2 of pramipexole hydrochloride. The modified Franz diffusion cell was used to measure the penetration rate of the transdermal patch in the abdominal skin of hair-free rats. The permeation rate of the pramipexole hydrochloride transdermal patch was 12.62ug/cm ² /h within 84 hours. The in vitro cumulative penetration curve is shown in Figure 2.

Example 3

The first layer (close to the anti-adhesive layer) composition: polyvinyl alcohol (PVA17-88) 0.6g, polyvinylpyrrolidone (PVP) 0.2g, menthol 0.2g, Tween 800.1g, glycerin 0.4g, sodium metabisulfite 0.05g, pramipexole hydrochloride 1.6mg.

The composition of the second layer (middle layer): polyvinyl alcohol (PVA17-88) 1.8g, polyvinylpyrrolidone (PVP) 0.3g, menthol 0.25g, Tween 800.1g, glycerin 0.5g, sodium metabisulfite 0.05g, general hydrochloride Laxole 6.4mg.

The composition of the third layer (close to the backing layer): polyvinyl alcohol (PVA17-88) 0.8g, polyvinylpyrrolidone (PVP) 0.1g, menthol 0.2g, Tween 800.1g, glycerin 0.4g, sodium metabisulfite 0.05g , pramipexole hydrochloride 3.2mg.

Prepared as in Example 1, prepared into a transdermal patch containing 2.04 mg/ ^cm2 of pramipexole hydrochloride. The modified Franz diffusion cell was used to measure the penetration rate of the transdermal patch in the abdominal skin of the hair-free rats. The permeation rate of the pramipexole hydrochloride transdermal patch was 6.88ug/cm ² /h within 84 hours. The in vitro cumulative permeation curve is shown in Figure 3.

Example 4

The composition of the first layer (close to the anti-sticking layer): polyvinyl alcohol (PVA17-88) 4.6g, polyvinylpyrrolidone (PVP) 1.0g, oleic acid 0.5g, propylene glycol 0.5g, glycerin 0.8g, glutathione Peptide 0.3g, pramipexole hydrochloride 20mg.

The composition of the second layer (middle layer): polyvinyl alcohol (PVA17-88) 3.6g, polyvinylpyrrolidone (PVP) 0.4g, oleic acid 0.8g, propylene glycol 0.4g, glycerin 0.6g, glutathione 0.4g, hydrochloric acid Pramipexole 40mg.

The composition of the third layer (close to the backing layer): polyvinyl alcohol (PVA17-88) 2.8g, polyvinylpyrrolidone (PVP) 0.8g, oleic acid 0.5g, propylene glycol 0.8g, glycerin 0.2g, glutathione 0.6 g, pramipexole hydrochloride 80mg.

Prepared as in Example 1, prepared into a transdermal patch containing pramipexole hydrochloride 1.96 mg/cm ² . The modified Franz diffusion cell was used to measure the penetration rate of the transdermal patch in the abdominal skin of the hair-free rats. The permeation rate of the pramipexole hydrochloride transdermal patch was 20.94ug/cm ² /h within 84 hours. The in vitro cumulative permeation curve is shown in Figure 4.

Claims (10)

1. a transdermal patch of pramipexole hydrochloride is made up of backing layer, drug-containing layer and anti-sticking layer, it is characterized in that, by weight, described drug-containing layer is made up of following component and weight ratio:

And the preparation method is to fully swell the hydrophilic polymer or viscous polymer with a solvent, add a penetration enhancer and a plasticizer to dissolve at a certain temperature, add a drug solution after the temperature drops, mix evenly, lay a film by casting, and dry to shape. For the multi-layer patch, prepare layer by layer, after drying and cooling, cover the backing layer and the anti-adhesive layer, and divide the preparation to complete. 2. A kind of pramipexole hydrochloride transdermal patch and preparation method thereof according to claim 1, characterized in that said drug-loaded material is selected from one or more of hydrophilic polymers and controlled-release membrane materials. wherein, the hydrophilic polymer is selected from one or more of polyvinyl alcohol, polyvinylpyrrolidone, polyacrylate or polyacrylamide; the controlled release film is preferably selected from microporous polypropylene or ethylene-acetic acid Ethylene copolymer. 3. a kind of pramipexole hydrochloride transdermal patch and preparation method thereof according to claim 1, is characterized in that, described penetration enhancer is selected from Tween 80, eucalyptus oil, n-octanol, azone, One or more of azone, ethanol, menthol, dibutyl sebacate, oleic acid, dimethyl sulfoxide, glycerol, sodium caprate, N-methylpyrrolidone or propylene glycol. 4. a kind of pramipexole hydrochloride transdermal patch and preparation method thereof according to claim 1, is characterized in that, described plasticizer is selected from glycerol, propylene glycol, sorbitol or polyethylene glycol one or two. 5. a kind of pramipexole hydrochloride transdermal patch and preparation method thereof according to claim 1, is characterized in that, described stabilizing agent is selected from disodium edetate, pyrosulfite, glutathione One or both of peptides, vitamin C, vitamin E. 6. a kind of pramipexole hydrochloride transdermal patch and preparation method thereof according to claim 1, is characterized in that, one layer of it is close to anti-adhesive layer contains drug-loaded material, penetration enhancer, plasticizer, Stabilizer and medicine, wherein the medicine accounts for 10-30% of the total medicine, the medicine contained in the three layers is 1 part of the juice, the weight of the polymer in this layer is 20-120 parts, and the weight of the penetration enhancer is 2-20 parts, The weight of the plasticizer is 1-30 parts, and the stabilizer is 1-30 parts. 7. a kind of pramipexole hydrochloride transdermal patch and preparation method thereof according to claim 1, is characterized in that, its middle layer does not contain medicine, only contains drug-loaded material, penetration enhancer and plasticizer, That is, the blank layer, based on 1 part of the drug contained in the three layers, the weight of the composition in this layer is 50-200 parts, the weight of the penetration enhancer is 4-50 parts, and the weight of the plasticizer is 2-40 parts. 8. a kind of pramipexole hydrochloride transdermal patch and preparation method thereof according to claim 1, is characterized in that, one layer of it is close to the backing layer containing drug-loaded material, penetration enhancer, plasticizer, Stabilizer and medicine, wherein the medicine contains 70-90% of the total medicine, the drug-loading material is preferably a hydrophilic polymer, and the medicine contained in the three layers is 1 part, and the weight of the composition in this layer is 30-180 parts, The weight of the penetration enhancer is 1-30 parts, the weight of the plasticizer is 2-40 parts, and the weight of the stabilizer is 2-50 parts. 9. a kind of pramipexole hydrochloride transdermal patch and preparation method thereof according to claim 1, is characterized in that, wherein medicine, drug-loaded material, penetration enhancer and plasticizer are mixed and made into three layers, three layers The drug, drug-loading material, penetration enhancer and plasticizer contained in the drug are different, and the drug content ratio of the layer close to the release layer, the middle layer and the backing layer is 1:1.5:3～1:5 :20. 10. A pramipexole hydrochloride transdermal patch and its preparation method according to claim 1, characterized in that the patch can maintain a constant rate of release with a permeation rate greater than 10ug/cm ² /h for a long time.

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