CN100469367C - Transdermal preparations comprising eperisone, tolperisone or salts thereof - Google Patents
Transdermal preparations comprising eperisone, tolperisone or salts thereof Download PDFInfo
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- CN100469367C CN100469367C CNB2003801012097A CN200380101209A CN100469367C CN 100469367 C CN100469367 C CN 100469367C CN B2003801012097 A CNB2003801012097 A CN B2003801012097A CN 200380101209 A CN200380101209 A CN 200380101209A CN 100469367 C CN100469367 C CN 100469367C
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- acryloid cement
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
Abstract
The present invention relates to transdermal preparations comprising eperisone, tolperisone or salts thereof, which is skeletal muscle relaxant, and more particularly, relates to transdermal preparations characterized in that, in delivering eperisone, tolperisone or its salts through skin, mixture of fixed ratio of acrylate adhesive having hydroxy group and acrylate adhesive without hydroxy group is used as a substrate, thereby maximizing percutaneous absorption of eperisone, tolperisone or salts thereof, raising the stability of eperisone, tolperisone or salts thereof, within substrate layer, and providing superior skin adhesion.
Description
Technical field
The present invention relates to comprise skeletal muscle relaxant eperisone, tolperisone or its salt preparation capable of permeating skin of (being called " eperisone etc. " hereinafter).
Background technology
Spasticity is because the neuronal degeneration of ischemic stroke, wound and several types following central nervous system pathological change appears, for example in a kind of skeletal muscle disease that the muscular tone increase causes.Because different neurotransmitter, neuromodulator, receptor and relevant ion channels participated in the interneuronal control of muscular tone, the muscle relaxant that acts on nervus centralis is generally used for treating spasm.By the antagonism receptor activation relevant or by acting on the receptor relevant with inhibit feature, the muscle relaxant that acts on nervus centralis can reduce the increase of muscular tone, and suppress the reflection of overacfivity with the excitement of motor function.Using this problem that acts on the muscle relaxant of nervus centralis is central nerve inhibition and muscle weakness.
Eperisones etc. are the muscle relaxants that acts on nervus centralis with low central nerve inhibition sickness rate, are widely used in treating muscle spasm, to alleviate myotonia and spondylalgia.Eperisones etc. go out loosening all muscles by acting on spinal cord and last nervus centralis level suppresses single synapse and multisynaptic reflex by reducing the muscular tone sex expression.But because the first-pass effect in absorption process, eperisone etc. show defective, the blood plasma level of promptly low-down bioavailability and variation.In addition,, need frequent drug administration, and all commercial products all are injection or oral formulations, existing problems aspect patient's compliance because the myorelaxant effects of absorbed eperisone etc. continues very shortly.
In order to address this problem, carry out many trials and developed preparation capable of permeating skin, medicine can enter in the body through skin surface thus.The 5th, 252,588 U.S. Patent Publications comprise eperisone and preparation capable of permeating skin that can water swellable crospolyvinylpyrrolidone.
With USP5,252,588 compare, preparation provided by the invention shows superior skin permeability, and when being attached to skin, has enough viscosity, good adhesion be can reach in whole application stages thus, and when removing, less pain and less skin peeling produced, therefore more convenient to the patient.
Summary of the invention
The purpose of this invention is to provide preparation capable of permeating skin, they have guaranteed the stability of the eperisone etc. in binding agent, have the skin adherence that is enough to use, and make medicine farthest pass through skin simultaneously.
The present invention relates to have the preparation capable of permeating skin of adhesion layer, described adhesion layer comprises the medicine that is selected from eperisone, tolperisone and its salt and as the acryloid cement with hydroxyl of binding agent and the mixture of the acryloid cement of hydroxyl not.
The medicine of Shi Yonging is selected from eperisone, tolperisone and their salt in the present invention, and as salt, hydrochlorate and phosphate are preferred.
Eperisone, tolperisone or its salt can be present in the binding agent with dissolving or crystal state, preferably, are 5～20 weight % with respect to this content of medicines of gross weight of adhesion layer.Usually, the skin permeability of known drug is along with the drug level in the binding agent increases pro rata.Therefore, cross when low, just can not see through the medicine of skin-communication q.s with the realization pharmacotoxicological effect when the drug level in the binding agent.But on the contrary, when drug level was too high, the increase of the dermal osmosis of medicine can not surpass certain level, and can influence the physical property of adhesion layer, and the skin adherence of preparation is had a negative impact.
The acryloid cement of Shi Yonging is made up of the acryloid cement with hydroxyl and the mixture of the acryloid cement of hydroxyl not in the present invention.Have the acryloid cement of hydroxyl and be preferably 8:2～5:5 with the weight mixing ratio of the acryloid cement of hydroxyl not.Described binding agent uses in the viscous liquid state that is added with organic solvent, evaporates only remaining acryloid cement in the dry run of most of organic solvents after being coated with the shop.
Acryloid cement with hydroxyl is used to make the dermal osmosis maximization of medicine.
Acryloid cement with hydroxyl is made up of the monomer with hydroxyl and the monomeric copolymer of hydroxyl not.
As monomer, can use to be selected from least a in (methyl) hydroxyethyl acrylate and (methyl) acrylic acid hydroxypropyl ester with hydroxyl.Preferably, the monomeric use amount with hydroxyl is preferably 1～20 weight % of the polymeric monomeric gross weight of acryloid cement that is used to have hydroxyl.
As the monomer of hydroxyl not, can use one or more monomers that are selected from common (methyl) alkyl acrylate monomer, for example butyl acrylate, acrylic acid methyl ester., methyl methacrylate and 2-ethylhexyl acrylate, acrylic acid and vinyl-acetic ester.
More specifically, as the monomer of hydroxyl not, preferably use 2-ethylhexyl acrylate and vinyl-acetic ester together, and the use amount of 2-ethylhexyl acrylate is preferably the 49-80 weight % of the acryloid cement gross weight with hydroxyl, and vinyl-acetic ester is preferably the 19-50 weight % of the acryloid cement gross weight with hydroxyl.
As the commercial product that the acryloid cement with hydroxyl is sold, can list (National Starch andChemical) such as Duro-Tak87-2287, Duro-Tak 87-2510 and Duro-Tak 87-2516.
In addition, with regard to the acryloid cement of hydroxyl not, because it does not contain the functional group with reaction such as medicine eperisone, thereby can improve the stability in binding agent such as eperisone, and therefore use with acryloid cement with hydroxyl.
The acryloid cement of described not hydroxyl is made up of common (methyl) alkyl acrylate monomer (for example butyl acrylate, acrylic acid methyl ester., methyl methacrylate and 2-ethylhexyl acrylate) and the monomeric copolymer of vinyl-acetic ester.Preferably, the acryloid cement of hydroxyl is not made up of 2-ethylhexyl acrylate and vinyl-acetic ester monomer, and 2-ethylhexyl acrylate is preferably the not 50-80 weight % of the acryloid cement gross weight of hydroxyl, and vinyl-acetic ester is preferably the not 20-50 weight amount % of the acryloid cement gross weight of hydroxyl.
As the commercial product of the acryloid cement of this not hydroxyl, can list Duro-Tak87-4098 (National Starch and Chemical),
Multipolymer Solution3067 and
Multipolymer Solution 3083 (SOLUTIA).
The common acryloid cement of Shi Yonging has carboxyl in the prior art.The monomer acrylic acid that uses in its next comfortable binding agent.This common acryloid cement only has carboxyl, perhaps has carboxyl and hydroxyl.As this acryloid cement, can list Duro-Tak 87-2074, Duro-Tak87-2194, Duro-Tak 87-2353, Duro-Tak 87-2677 and Duro-Tak 87-2825 (National Starch and Chemical), as acryloid cement with amide groups, can list Duro-Tak 87-9301 (National Starch and Chemical), the acryloid cement that has vinylpyrrolidone in addition, for example TSR (Sekisui).This acryloid cement is not used among the present invention, but as contrast.
Can contain other solubilizing agent according to preparation of the present invention, to improve the content in adhesion layer such as eperisone.
In the present invention, to be used to make key component wherein be that the adhesion layer of acryloid cement contains the eperisone of determining concentration etc. in solubilizing agent.As this solubilizing agent, can list distilled water, ethanol, isopropyl alcohol, TC, Polyethylene Glycol, glycerol and dimethyl sulfoxide, can use wherein one or more, and its consumption is preferably the 1-20 weight % of adhesion layer gross weight.
Correspondingly, preparation of the present invention can further contain dermal osmosis accelerator, to improve the percutaneous absorption rate of eperisone etc.
As the dermal osmosis accelerator that uses in the present invention, can list for example oleic acid of higher fatty acids, higher alcohol is lauryl alcohol for example, high-grade aliphatic ester is isopropyl myristate for example, the fatty acid ester of glycerol is glyceryl monolaurate for example, the fatty acid ether of Polyethylene Glycol is polyethylene glycol lauryl ether for example, the fatty acid ester of Polyethylene Glycol is polyethylene glycol laurate for example, the fatty acid ether of propylene glycol is the propylene glycol lauryl ether for example, the fatty acid ester of propylene glycol is the propylene glycol laurate for example, fatty acid esters of sorbitan is Arlacel-20 for example, the Polyethylene Glycol fatty acid esters of sorbitan is the Polyethylene Glycol Arlacel-20 for example, terpene is menthol for example, menthol derivative and limonene, sulfoxide is dimethyl sulfoxide for example, the dodecyl sulfoxide, ketopyrrolidine is the N-N-methyl-2-2-pyrrolidone N-for example, amide is the lauryl diglycollic amide for example, N-hydroxymethyl lactide, sorbitol, urea, Squalene, olive oil, mineral oil and their derivant, can use wherein one or more, and be preferably the 1-20 weight % of adhesion layer gross weight.
As the back lining materials of preparation capable of permeating skin, can use the back lining materials that uses as in conventional preparation capable of permeating skin according to the present invention.For example, can use the material that air and moisture is had good permeability, for example non-woven fabrics, cotton and fabric, or polyethylene terephthalate, polyurethanes, polyethylene, polypropylene, ethylene vinyl acetate and close thin film or multilamellar is closed thin film through the poly monolayer that aluminum is handled, use if desired, can be with non-woven fabrics or cotton and fluid-tight plastic foil lamination.
The preparation capable of permeating skin that comprises eperisone etc. according to the present invention is characterised in that it is patch matrix type or medicine (drug-in-adhesive) type in binding agent.With regard to this patch, its dosage form and plaster and cataplasma do not have too big difference, therefore can make the form of plaster or cataplasma.
The specific embodiment
Below, explain the present invention by embodiment and EXPERIMENTAL EXAMPLE, but the present invention is not subjected to their restriction.
Comparative Examples 1-1
Composition
Tolperisone hydrochloride 20 weight %
Glyceryl monolaurate 5 weight %
Polyethylene Glycol (400) 5 weight %
Acryloid cement (Duro-Tak 87-2194) 70 weight % (dry weight)
Here, dry weight is meant the weight that the organic solvent evaporation that contains obtains later in described adhesive product.
Method
1. tolperisone hydrochloride, glyceryl monolaurate and Polyethylene Glycol (400) are joined in the acryloid cement, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 25 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. laminated polyethylene film.
Comparative Examples 1-2
Composition
Tolperisone hydrochloride 20 weight %
Glyceryl monolaurate 5 weight %
Polyethylene Glycol (400) 5 weight %
Acryloid cement (Duro-Tak 87-9301) 70 weight % (dry weight)
Method
1. tolperisone hydrochloride, glyceryl monolaurate and Polyethylene Glycol (400) are joined in the acryloid cement, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 25 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. laminated polyethylene film.
Comparative Examples 1-3
Composition
Tolperisone hydrochloride 20 weight %
Glyceryl monolaurate 5 weight %
Polyethylene Glycol (400) 5 weight %
Acryloid cement (
70 weight % (dry weight)
Multipolymer Solution 3083)
Method
1. tolperisone hydrochloride, glyceryl monolaurate and Polyethylene Glycol (400) are joined in the acryloid cement, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 25 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. laminated polyethylene film.
Comparative Examples 1-4
Composition
Tolperisone hydrochloride 20 weight %
Glyceryl monolaurate 5 weight %
Polyethylene Glycol (400) 5 weight %
Acryloid cement (Duro-Tak 87-2516) 70 weight % (dry weight)
Method
1. tolperisone hydrochloride, glyceryl monolaurate and Polyethylene Glycol (400) are joined in the acryloid cement, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 25 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. laminated polyethylene film.
Comparative Examples 2-1
Composition
E-646 5 weight %
Polyoxyethylene (2) lauryl ether 3 weight %
Propylene glycol 5 weight %
Acryloid cement (Duro-Tak 87-2074) 87 weight % (dry weight)
Method
1. E-646, polyoxyethylene (2) lauryl ether and propylene glycol are joined in the acryloid cement, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 100 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. laminated polyethylene film.
Comparative Examples 2-2
Composition
E-646 5 weight %
Polyoxyethylene (2) lauryl ether 3 weight %
Propylene glycol 5 weight %
Acryloid cement (Duro-Tak 87-2353) 87 weight % (dry weight)
Method
1. E-646, polyoxyethylene (2) lauryl ether and propylene glycol are joined in the acryloid cement, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 100 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. laminated polyethylene film.
Comparative Examples 2-3
Composition
E-646 5 weight %
Polyoxyethylene (2) lauryl ether 3 weight %
Propylene glycol 5 weight %
Acryloid cement (Duro-Tak 87-4098) 87 weight % (dry weight)
Method
1. E-646, polyoxyethylene (2) lauryl ether and propylene glycol are joined in the acryloid cement, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 100 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. laminated polyethylene film.
Comparative Examples 2-4
Composition
E-646 5 weight %
Polyoxyethylene (2) lauryl ether 3 weight %
Propylene glycol 5 weight %
Acryloid cement (Duro-Tak 87-2510) 87 weight % (dry weight)
Method
1. E-646, polyoxyethylene (2) lauryl ether and propylene glycol are joined in the acryloid cement, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 100 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. laminated polyethylene film.
Comparative Examples 3
Composition
E-646 10 weight %
Polyvidone INF-10 5 weight %
Acryloid cement (TSR) 85 weight % (dry weight)
Method
1. E-646 and polyvidone INF-10 are joined in the acryloid cement, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 50 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. layered polyester film.
Comparative Examples 4-1
Composition
E-646 10 weight %
PGML 2.5 weight %
TC 2.5 weight %
Acryloid cement (Duro-Tak 87-4098) 85 weight % (dry weight)
Method
1. E-646, PGML and TC are joined in the acryloid cement, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 50 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. layered polyester film.
Comparative Examples 4-2
Composition
E-646 10 weight %
PGML 2.5 weight %
TC 2.5 weight %
Acryloid cement (Duro-Tak 87-2287) 85 weight % (dry weight)
Method
1. E-646, PGML and TC are joined in the acryloid cement, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 50 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. layered polyester film.
Comparative Examples 4-3
Composition
E-646 10 weight %
PGML 2.5 weight %
TC 2.5 weight %
Acryloid cement (Duro-Tak 87-2287) 25.5 weight % (dry weight)
Acryloid cement (Duro-Tak 87-4098) 59.5 weight % (dry weight)
Method
1. E-646, PGML and TC are mixed with two kinds of acryloid cements, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 50 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. layered polyester film.
Comparative Examples 4-4
Composition
E-646 10 weight %
PGML 2.5 weight %
TC 2.5 weight %
Acryloid cement (Duro-Tak 87-2287) 34 weight % (dry weight)
Acryloid cement (Duro-Tak 87-4098) 51 weight % (dry weight)
Method
1. E-646, PGML and TC are mixed with two kinds of acryloid cements, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 50 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. layered polyester film.
Embodiment 1
Composition
E-646 10 weight %
PGML 2.5 weight %
TC 2.5 weight %
Acryloid cement (Duro-Tak 87-2287) 42.5 weight % (dry weight)
Acryloid cement (Duro-Tak 87-4098) 42.5 weight % (dry weight)
Method
1. E-646, PGML and TC are mixed with two kinds of acryloid cements, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 50 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. layered polyester film.
Embodiment 2
Composition
E-646 10 weight %
PGML 2.5 weight %
TC 2.5 weight %
Acryloid cement (Duro-Tak 87-2287) 51 weight % (dry weight)
Acryloid cement (Duro-Tak 87-4098) 34 weight % (dry weight)
Method
1. E-646, PGML and TC are mixed with two kinds of acryloid cements, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 50 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. layered polyester film.
Embodiment 3
Composition
E-646 10 weight %
PGML 2.5 weight %
TC 2.5 weight %
Acryloid cement (Duro-Tak 87-2287) 59.5 weight % (dry weight)
Acryloid cement (Duro-Tak 87-4098) 25.5 weight % (dry weight)
Method
1. E-646, PGML and TC are mixed with two kinds of acryloid cements, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 50 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. layered polyester film.
Embodiment 4
Composition
Tolperisone hydrochloride 10 weight %
PGML 2.5 weight %
PEG400 2.5 weight %
Acryloid cement (Duro-Tak 87-2287) 59.5 weight % (dry weight)
Acryloid cement (Duro-Tak 87-4098) 25.5 weight % (dry weight)
Method
1. tolperisone hydrochloride, PGML and PEG400 are mixed with two kinds of acryloid cements, make dissolving fully by stirring.
2. described mixture is coated with and is taped against on the release liner, making dried thickness is 50 μ m.
3. in 80 ℃, drying is 20 minutes in baking oven.
4. layered polyester film.
EXPERIMENTAL EXAMPLE 1: percutaneous permeability experiment
With the hair shears hair of male guinea pig (350g) abdominal part is cut, removed fully with razor, take off the intact skin of ideal abdominal part position, freezing (being lower than 20 ℃) storage is in order to the usefulness of experiment in the future.
Be cut into 2 * 2cm after skin thawed
2Size is cut into 1.5 * 1.5cm with the patch for preparing among Comparative Examples and the embodiment
2Size is attached on the horny layer.
Skin is fixed on the Frantz type diffusion cell by the part mode up that patch attaches, and the buffer of required pH is equipped with in the bottom of device, and diffusion cell maintains 37 ℃.Stir reception liquid (buffer) with 600rpm.After the time of determining, take out a certain amount of reception liquid, and be packed into the fresh buffer of equivalent.Sample is carried out HPLC analyze, the result is as shown in table 1.
Table 1 penetrates the amount of eperisone in the preparation capable of permeating skin of guinea pig skin etc.
| The patch numbering | Through 24 hours infiltration capacities (μ g/cm 2) |
| Comparative Examples 1-1 | 52.5 |
| Comparative Examples 1-2 | 68.3 |
| Comparative Examples 1-3 | 33.0 |
| Comparative Examples 1-4 | 107.1 |
| Comparative Examples 2-1 | 42.9 |
| Comparative Examples 2-2 | 76.7 |
| Comparative Examples 2-3 | 35.2 |
| Comparative Examples 2-4 | 118.1 |
| Comparative Examples 3 | 78.5 |
| Comparative Examples 4-1 | 50.3 |
| Comparative Examples 4-2 | 122.2 |
| Comparative Examples 4-3 | 62.9 |
| Comparative Examples 4-4 | 80.2 |
| Embodiment 1 | 83.6 |
| Embodiment 2 | 92.4 |
| Embodiment 3 | 102.8 |
| Embodiment 4 | 98.3 |
Can determine from top table 1, use the flow-rate ratio of the patch of acryloid cement to use the patch of other acryloid cement higher with hydroxyl.
In addition, containing acryloid cement and not in the patch of the acryloid cement of hydroxyl with hydroxyl, use high concentration the acryloid cement with hydroxyl patch for example embodiment 1 to 3 show than the better flow of other patch.
EXPERIMENTAL EXAMPLE 2: peel off experiment
According to the PSTC-1 experimental technique, measure peel strength with fabric analysis instrument (textile analyzer) (TX2, MHKTrading co.).The patch of preparation is cut into 2.5cm * 10cm size, is attached at stainless steel-based the end, measure peel strength with constant speed desorption the time, the result is as shown in table 2.
Table 2 peel strength
| The patch numbering | Peel strength (g power) |
| Comparative Examples 1-4 | 1345 |
| Comparative Examples 2-4 | 1587 |
| Comparative Examples 3 | 1261 |
| Comparative Examples 4-2 | 1337 |
| Embodiment 2 | 748 |
| Embodiment 3 | 839 |
Can determine from top table 2, with regard to Comparative Examples 1-4,2-4,3 and 4-2 with regard to, too high peel strength causes patient's pain probably from skin removed the time, also can increase skin irritation owing to cuticular damage and physical stimulation.On the contrary, embodiment 2 and 3 shows suitable peel strength, and it can be reduced in when sticking patch the probability from falling out, and peels off easily when removing.
Embodiment 3: stability experiment
The patch of preparation is put into aluminum packing, charge into nitrogen, under 40 ℃, relative humidity 75% condition, in baking oven, store.After the time of determining, unpack, take out medicine, measure its residual volume.The result is as shown in table 3.
The residual volume of the eperisone in table 3 patch etc.
From top table 3 as can be seen, eperisone etc. is the most stable in using the patch of the Comparative Examples 1-3 of the acryloid cement of hydroxyl not.Only use Comparative Examples 1-4, the 2-4 of acryloid cement and the patch of 4-2 to have stability problem with hydroxyl.But as the result with the described two kinds of binding agents of suitable mixed, stability is improved, thereby can not go wrong in the storage of reality.
Industrial applicibility
The present invention relates to comprise the preparation capable of permeating skin of nervous centralis skeletal muscle relaxant Eperisone etc., compare with oral formulations or the injection of routine, the action time of its energy prolong drug, thereby so that exploitation once-a-day or the next day once preparation become possibility, and show than the better percutaneous permeability of the preparation of existing patent Introduction, thereby the preparation capable of permeating skin of smaller szie is provided.
Claims (8)
1. the preparation capable of permeating skin that has adhesion layer, described adhesion layer comprise be selected from eperisone, tolperisone with and the medicine of salt and as the acryloid cement that only has hydroxyl and the mixture that does not contain the acryloid cement of functional group of binding agent;
Be 5～20 weight % wherein with respect to the described content of medicines of the gross weight of adhesion layer;
It is described that only to have the acryloid cement of hydroxyl be 8:2～5:5 with the mixing ratio that does not contain the acryloid cement of functional group;
The wherein said acryloid cement that only has hydroxyl is to have the monomer of hydroxyl and the monomeric random copolymer that does not contain functional group;
Described monomer with hydroxyl is to be selected from least a in (methyl) hydroxyethyl acrylate and (methyl) acrylic acid hydroxypropyl ester;
The described monomer that does not contain functional group is at least a monomer that is selected from (methyl) alkyl acrylate monomer and the vinyl-acetic ester; And
The described acryloid cement that does not contain functional group is made up of (methyl) alkyl acrylate monomer and vinyl-acetic ester.
2. according to the preparation capable of permeating skin of claim 1, wherein said salt is hydrochlorate or phosphate.
3. according to the preparation capable of permeating skin of claim 1, wherein said monomer with hydroxyl occupies 1～20 weight % that polymerization generates the monomeric gross weight of the acryloid cement that only has hydroxyl.
4. according to the preparation capable of permeating skin of claim 1, the wherein said monomer that does not contain functional group is 2-ethylhexyl acrylate and vinyl-acetic ester, and the content of this 2-ethylhexyl acrylate is for only having the 49-80 weight % of the acryloid cement gross weight of hydroxyl, and the content of this vinyl-acetic ester is 19-50 weight %.
5. according to the preparation capable of permeating skin of claim 1, the wherein said acryloid cement that does not contain functional group is made up of 2-ethylhexyl acrylate and vinyl-acetic ester, and the content of this 2-ethylhexyl acrylate is the 50-80 weight % that does not contain the acryloid cement gross weight of functional group, and the content of this vinyl-acetic ester is 20-50 weight %.
6. according to the preparation capable of permeating skin of claim 1, it is characterized in that it also contains at least a solubilizing agent that is selected from following group in the 1-20 of adhesion layer gross weight weight % scope: distilled water, ethanol, isopropyl alcohol, TC, Polyethylene Glycol, glycerol and dimethyl sulfoxide.
7. according to the preparation capable of permeating skin of claim 1, it is characterized in that it also contains at least a dermal osmosis accelerator that is selected from following group in the 1-20 of adhesion layer gross weight weight % scope: higher fatty acids, higher alcohol, high-grade aliphatic ester, the fatty acid ester of glycerol, the fatty acid ether of Polyethylene Glycol, the fatty acid ester of Polyethylene Glycol, the fatty acid ether of propylene glycol, the fatty acid ester of propylene glycol, fatty acid esters of sorbitan, the Polyethylene Glycol fatty acid esters of sorbitan, terpene, sulfoxide, ketopyrrolidine, amide, N-hydroxymethyl lactide, sorbitol, urea, Squalene, olive oil, mineral oil and their derivant.
8. preparation capable of permeating skin according to claim 7, wherein said higher fatty acids is an oleic acid, described higher alcohol is a lauryl alcohol, described high-grade aliphatic ester is an isopropyl myristate, the fatty acid ester of described glycerol is the glyceryl monolaurate, the fatty acid ether of described Polyethylene Glycol is polyethylene glycol lauryl ether, the fatty acid ester of described Polyethylene Glycol is a polyethylene glycol laurate, the fatty acid ether of described propylene glycol is the propylene glycol lauryl ether, the fatty acid ester of described propylene glycol is the propylene glycol laurate, described fatty acid esters of sorbitan is an Arlacel-20, described Polyethylene Glycol fatty acid esters of sorbitan is the Polyethylene Glycol Arlacel-20, described terpene is a menthol, menthol derivative and limonene, described sulfoxide is dimethyl sulfoxide and dodecyl sulfoxide, described ketopyrrolidine is the N-N-methyl-2-2-pyrrolidone N-, and described amide is the lauryl diglycollic amide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020020061972 | 2002-10-11 | ||
| KR10-2002-0061972A KR100511492B1 (en) | 2002-10-11 | 2002-10-11 | Transdermal preparations comprising eperisone, tolperisone or salts thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1703219A CN1703219A (en) | 2005-11-30 |
| CN100469367C true CN100469367C (en) | 2009-03-18 |
Family
ID=32089699
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2003801012097A Expired - Fee Related CN100469367C (en) | 2002-10-11 | 2003-10-10 | Transdermal preparations comprising eperisone, tolperisone or salts thereof |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JP2006503877A (en) |
| KR (1) | KR100511492B1 (en) |
| CN (1) | CN100469367C (en) |
| AU (1) | AU2003269511A1 (en) |
| WO (1) | WO2004032927A1 (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050058673A1 (en) | 2003-09-09 | 2005-03-17 | 3M Innovative Properties Company | Antimicrobial compositions and methods |
| JP2006151927A (en) * | 2004-12-01 | 2006-06-15 | Toin Gakuen | Photodynamic therapy composition |
| ATE511838T1 (en) | 2005-03-10 | 2011-06-15 | 3M Innovative Properties Co | ANTIMICROBIAL COMPOSITIONS CONTAINING HYDROXYCARBOXYLIC ACID ESTERS |
| US20060229364A1 (en) * | 2005-03-10 | 2006-10-12 | 3M Innovative Properties Company | Antiviral compositions and methods of use |
| JP5642929B2 (en) | 2005-03-10 | 2014-12-17 | スリーエム イノベイティブ プロパティズ カンパニー | Method for reducing minute biological contamination |
| AT505225A1 (en) | 2007-04-26 | 2008-11-15 | Sanochemia Pharmazeutika Ag | Tolperisone and their pharmaceutical acceptable salts and hydrates production for use as active substance in pharmaceutical formulation for drugs, for treatment and therapy of Alzheimer's disease, involves converting methylpropiophenone |
| CN102438597A (en) | 2009-03-09 | 2012-05-02 | 丁内沙·沙蒂尔阿尔·帕特尔 | A novel sustained release composition of compounds selected from the class of centrally acting muscle relaxants |
| KR101832842B1 (en) * | 2012-01-13 | 2018-02-27 | 한미약품 주식회사 | Pharmaceutical composition with an improved stability comprising eperisone or a pharmaceutically acceptable salt thereof and specific acidifying agent |
| JP6188933B2 (en) | 2013-10-07 | 2017-08-30 | テイコク ファーマ ユーエスエー インコーポレーテッド | Methods and compositions for transdermal delivery of non-sedating amounts of dexmedetomidine |
| JP6310070B2 (en) | 2013-10-07 | 2018-04-11 | テイコク ファーマ ユーエスエー インコーポレーテッド | Therapeutic methods and compositions for attention deficit / hyperactivity disorder, anxiety and insomnia using dexmedetomidine transdermal composition |
| CN110604728A (en) * | 2013-10-07 | 2019-12-24 | 帝国制药美国公司 | Methods and compositions comprising dexmedetomidine transdermal compositions for managing pain |
| WO2015054058A1 (en) | 2013-10-07 | 2015-04-16 | Teikoku Pharma Usa, Inc. | Dexmedetomidine Transdermal Delivery Devices and Methods for Using the Same |
| JP6654365B2 (en) * | 2015-06-17 | 2020-02-26 | 日東電工株式会社 | Patch preparation |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2693212B2 (en) * | 1989-03-28 | 1997-12-24 | 日東電工株式会社 | Tape preparation for disease treatment |
| JPH03141223A (en) * | 1989-10-26 | 1991-06-17 | Nitto Denko Corp | External preparation |
| JPH04182424A (en) * | 1990-11-16 | 1992-06-30 | Nitto Denko Corp | Plaster containing eperisone |
| JPH0640917A (en) * | 1991-06-21 | 1994-02-15 | Nichiban Co Ltd | Cataplasm containing tolperisone or eperisone |
| KR930007407A (en) * | 1991-10-10 | 1993-05-20 | 이헌조 | Apparatus and Method for Automatic Determination of Appropriate Quantity of Cooker |
| JPH08291067A (en) * | 1995-04-21 | 1996-11-05 | Sekisui Chem Co Ltd | Eperisone plaster for external use |
| JP4145996B2 (en) * | 1998-08-03 | 2008-09-03 | 日東電工株式会社 | Acrylic adhesive tape and transdermal absorption preparation |
| KR100433614B1 (en) * | 2000-06-16 | 2004-05-31 | 주식회사 태평양 | Transdermal Preparation Containing Hydrophilic or Salt-form Drug |
-
2002
- 2002-10-11 KR KR10-2002-0061972A patent/KR100511492B1/en not_active IP Right Cessation
-
2003
- 2003-10-10 WO PCT/KR2003/002086 patent/WO2004032927A1/en active Application Filing
- 2003-10-10 JP JP2004542906A patent/JP2006503877A/en active Pending
- 2003-10-10 AU AU2003269511A patent/AU2003269511A1/en not_active Abandoned
- 2003-10-10 CN CNB2003801012097A patent/CN100469367C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| KR100511492B1 (en) | 2005-08-31 |
| CN1703219A (en) | 2005-11-30 |
| KR20040033082A (en) | 2004-04-21 |
| WO2004032927A1 (en) | 2004-04-22 |
| AU2003269511A1 (en) | 2004-05-04 |
| JP2006503877A (en) | 2006-02-02 |
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| C06 | Publication | ||
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| SE01 | Entry into force of request for substantive examination | ||
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Granted publication date: 20090318 Termination date: 20091110 |