CN112438963A

CN112438963A - External preparation of lidocaine-prilocaine pharmaceutical composition and application thereof

Info

Publication number: CN112438963A
Application number: CN202011254465.1A
Authority: CN
Inventors: 张海龙; 黄雅倩
Original assignee: Changsha Jingyi Medical Technology Co ltd
Current assignee: Changsha Jingyi Medical Technology Co ltd
Priority date: 2020-11-11
Filing date: 2020-11-11
Publication date: 2021-03-05
Also published as: WO2022100120A1

Abstract

The invention discloses an external preparation of a lidocaine-prilocaine medicinal composition, wherein the content of the lidocaine-prilocaine medicinal composition is 1% -10%. The external preparation comprises a patch containing lidocaine-prilocaine oily eutectic substance, a non-hydrophilic matrix material and pharmaceutically acceptable external preparation auxiliary materials, and a gel plaster containing lidocaine-prilocaine O/W type microemulsion, a hydrophilic gel matrix material and pharmaceutically acceptable external preparation auxiliary materials. The patch and gel plaster can be used for topical superficial anesthesia or relieving pain after injection, pain after puncture, pain caused by intravenous retention needle, postherpetic neuralgia, and pain due to intervertebral disc prolapse. The invention has the advantages that the lidocaine-prilocaine eutectic is used as an active ingredient, the percutaneous permeation rate and the absorption degree of the lidocaine and the prilocaine can be obviously improved, the beneficial effect of synergy is generated, the incidence rate of toxic and side effects of the lidocaine and the prilocaine is reduced, and a new choice is provided for pain easing and anesthesia requirements of patients and medical staff.

Description

External preparation of lidocaine-prilocaine pharmaceutical composition and application thereof

Technical Field

The invention relates to the field of pharmaceutical preparations, in particular to an external preparation of a lidocaine-prilocaine pharmaceutical composition and application thereof.

Background

Pain is a defining feature of many disease diagnoses and is an unpleasant sensation and experience. When the external stimulus intensity reaches a threshold value, nociceptive sensory fibers are activated to generate nerve impulses, and the nerve impulses are transmitted to the spinal cord and the center through afferent nerves to generate reflex response and pain sensation. Common pain types include protective pain, inflammatory pain, and neuropathic pain resulting from acupuncture, heat, compression, and the like. Pain can last for hours, days or even years, not only reducing the quality of life of the patient, but also severely affecting their mental and physical health.

The means for relieving pain mainly comprises oral analgesic drugs and local injection anesthetic drugs to reduce the generation of nerve impulses or block the conduction of nerve impulses. However, oral administration has a long onset time, generally has strong gastrointestinal side effects or other adverse reactions, and is not suitable for long-term administration. Local injection of anesthetic must be performed by medical personnel, which is liable to cause pain at the injection site and poor patient compliance. In addition, if local anesthetic is used in an overdose, risks of producing systemic anesthesia, central toxicity and cardiotoxicity are greatly increased, and safety is low. Therefore, although partial examination or surgery has been performed for the purpose of local anesthesia or analgesia by local application of anesthetic drugs, the dosage form is limited in use space due to imprecise dosage and failure to continuously permeate for a long time. The transdermal patch has the advantages of accurate dosage, noninvasive and painless administration, gastrointestinal side effect and first pass effect avoidance, administration frequency reduction and the like, and improves administration safety and patient compliance.

Currently, gel patches of local anesthetic lidocaine have been used in countries such as europe and the united states as a first-line treatment for postherpetic neuralgia. Research shows that when lidocaine gel plaster is applied to skin, the medicine release rate is slow, and the residual quantity in the plaster is large, so that the utilization rate of active ingredients is low. In addition, liver metabolites of lidocaine also have anesthetic, antiarrhythmic activity similar to that of the active ingredient, and if used in excess, the risk of adverse reactions is greater. The lidocaine is used in combination with other medicines, so that the dosage of the lidocaine can be reduced, the incidence rate of adverse reactions is reduced, and the purpose of synergism can be realized.

Creams and gels of lidocaine-prilocaine pharmaceutical compositions have been approved for superficial analgesia and for local anesthesia of the oral cavity. Prilocaine and lidocaine are similar and belong to amide local anesthetics, and both can block the generation and conduction of nerve impulses by blocking sodium ion channels and limiting the inflow of sodium ions, thereby playing the role of local anesthesia or analgesia. The lidocaine and prilocaine can form an oily eutectic substance in a certain proportion. Research shows that compared with the two eutectic compounds used alone, the eutectic compound has obviously raised transdermal permeation rate and absorption degree, and thus raised medicine effect. And the combination of the lidocaine and the prilocaine reduces the usage amount of the lidocaine and the prilocaine, reduces the adverse reaction and the toxic and side effect incidence rate of the lidocaine and the prilocaine, and improves the administration safety. However, the gel and the cream cannot stay for a long time when being used and are easy to be erased by clothes; if the packet is performed, the operation is complicated. In conclusion, the existing preparation of the lidocaine-prilocaine pharmaceutical composition still has certain defects.

Disclosure of Invention

In view of the above, the main objective of the present invention is to provide an external preparation of lidocaine-prilocaine pharmaceutical composition and its application for local superficial anesthesia or local pain relief.

The technical scheme of the invention is as follows:

the invention provides an external preparation of a lidocaine-prilocaine medicinal composition, which comprises lidocaine, prilocaine, a framework matrix material and pharmaceutically acceptable external preparation auxiliary materials, and is characterized in that the content of the lidocaine-prilocaine medicinal composition in the external preparation is 1% -10%. Wherein the lidocaine-prilocaine pharmaceutical composition is present as an oily eutectic.

The external preparation comprises a patch and a gel plaster. Wherein the lidocaine-prilocaine pharmaceutical composition is present in the patch as an oily eutectic; the lidocaine-prilocaine pharmaceutical composition exists in the gel plaster in O/W type microemulsion.

The formula of the patch comprises lidocaine, prilocaine, a non-hydrophilic matrix material and pharmaceutically acceptable external preparation auxiliary materials, and the formula of the gel plaster comprises lidocaine, prilocaine, an emulsifier, a hydrophilic gel matrix material and pharmaceutically acceptable external preparation auxiliary materials.

The external preparation is added with a skeleton matrix material in the prescription composition, and comprises a hydrophilic gel matrix material and a non-hydrophilic matrix material. Wherein the non-hydrophilic matrix material comprises solvent type, emulsion type and hot melt type matrix materials.

The hydrophilic gel matrix material includes but is not limited to one or more of gelatin, acacia, polyacrylic acid with different polymerization degrees and sodium salt thereof, sodium carboxymethyl cellulose, carbomer, polyvinyl alcohol and polyvinylpyrrolidone.

The non-hydrophilic matrix material includes but is not limited to one or more of polyacrylate and its derivatives, styrene-isoprene-styrene block copolymer (SIS), polyisobutylene and its derivatives, silicone rubber, and silicone.

The formula of the external preparation is added with pharmaceutically acceptable external preparation auxiliary materials, including but not limited to one or more of a tackifier, a humectant, a transdermal enhancer, an emulsifier, an antioxidant, a filler and a preservative.

Tackifiers include, but are not limited to, one or more of terpene resins, polystyrene resins, rosin resins.

Humectants include, but are not limited to, one or more of glycerin, sorbitol, allantoin, polyethylene glycol.

The transdermal enhancer includes, but is not limited to, one or more of propylene glycol, isopropyl myristate, isopropyl palmitate, and menthol.

The emulsifier includes but is not limited to one or more of polysorbate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, glyceryl monostearate and phospholipid.

Antioxidants include, but are not limited to, one or more of dibutylhydroxytoluene, tocopherol, ascorbic acid, and salts thereof.

Fillers include, but are not limited to, one or more of kaolin, titanium dioxide, calcium carbonate, silicic acid.

Preservatives include, but are not limited to, one or more of methylparaben, ethylparaben, propylparaben.

In the external preparation, the prescription composition of the drug-containing layer of the patch includes but is not limited to:

1 to 10 percent of lidocaine

Prilocaine 1% -10%

Polyacrylate (DURO-TAK 180-129A) 10% -50%

5 to 15 percent of tocopherol

0 to 20 percent of kaolin

0.1 to 5 percent of propylene glycol

0.1 to 5 percent of methyl p-hydroxybenzoate.

1 to 10 percent of lidocaine

Prilocaine 1% -10%

SIS D1163P 10%-50%

10 to 30 percent of terpene resin

20 to 30 percent of liquid paraffin

5 to 15 percent of butylated hydroxytoluene

0 to 20 percent of kaolin

0.1 to 5 percent of propylene glycol

0.1 to 5 percent of methyl p-hydroxybenzoate.

In the external preparation, the prescription composition of the medicine-containing layer of the gel plaster comprises but is not limited to:

1 to 10 percent of lidocaine

Prilocaine 1% -10%

Polysorbate-8010% -30%

Sodium polyacrylate NP-70010-50%

10 to 30 percent of polyvinyl alcohol

10 to 15 percent of glycerin

0.1 to 5 percent of propylene glycol

0 to 5 percent of dihydroxyaluminium aminoacetate

0 to 20 percent of kaolin

0.1 to 5 percent of methyl p-hydroxybenzoate

40-60% of purified water.

The external preparation of the invention can be used for local superficial anesthesia or local pain relief. Preferably, the composition can be used for relieving local pain such as pain after injection, pain after puncture, pain caused by intravenous indwelling needle, postherpetic neuralgia, and pain caused by touch due to intervertebral disc protrusion.

The invention has the advantages that:

the invention provides an external patch and a gel plaster of a lidocaine-prilocaine medicinal composition, which can be used for local superficial anesthesia or local pain relief. The combination of lidocaine and prilocaine can reduce the usage amount of lidocaine and prilocaine, thereby reducing the incidence rate of toxic and side effects. In addition, in the invention, the pharmaceutical composition of lidocaine and prilocaine exists in the external preparation in the form of oily eutectic substance, so that the transdermal penetration rate and the absorption degree of the lidocaine and prilocaine can be improved, and a synergistic effect is generated. Based on the above, the external preparation of the lidocaine-prilocaine pharmaceutical composition provided by the invention has good safety and high drug utilization rate, and provides a new choice for pain relieving and anesthesia requirements of patients and medical staff.

Drawings

FIG. 1 shows the change in the negative response to needle stimulation after administration to each experimental group.

Detailed Description

In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, but rather should be construed as broadly as the present invention is capable of modification in various respects, all without departing from the spirit and scope of the present invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

Example 1: lidocaine-prilocaine patch (solvent type substrate)

The prescription composition is as follows:

the preparation process comprises the following steps: taking lidocaine and prilocaine with the prescription amount into a container, heating to 40-50 ℃, stirring and uniformly mixing until the lidocaine and the prilocaine are completely melted to form transparent oily eutectic liquid. Taking DURO-TAK 180-129A, kaolin, tocopherol, propylene glycol, methyl p-hydroxybenzoate and lidocaine-prilocaine oil eutectic substances in the prescription amount into a mixing container, and stirring and mixing uniformly to obtain a medicine-containing layer. And uniformly coating the medicine-containing layer on a polyethylene glycol terephthalate (PET) film, attaching the PET film to a non-woven fabric, and cutting the PET film into required sizes to obtain the lidocaine-prilocaine patch.

Example 2: lidocaine-prilocaine patch (Hot melt type matrix)

The prescription composition is as follows:

the preparation process comprises the following steps: taking lidocaine and prilocaine with the prescription amount into a container, heating to 40-50 ℃, stirring and uniformly mixing until the lidocaine and the prilocaine are completely melted to form transparent oily eutectic liquid. Taking the formula amount of SIS D1163P, terpene resin, liquid paraffin, dibutyl hydroxy toluene, kaolin, propylene glycol and methyl p-hydroxybenzoate, heating to 150 ℃ to melt and uniformly mixing. And then adding the lidocaine-prilocaine oily eutectic into a mixing container, and stirring and mixing uniformly to obtain a medicine-containing layer. And uniformly coating the medicine-containing layer on a polyethylene glycol terephthalate (PET) film, attaching the PET film to a non-woven fabric, and cutting the PET film into required sizes to obtain the lidocaine-prilocaine patch.

Example 3: lidocaine-prilocaine gel plaster

The prescription composition is as follows:

the preparation process comprises the following steps: taking lidocaine and prilocaine with the prescription amount into a container, heating to 40-50 ℃, stirring and uniformly mixing until the lidocaine and the prilocaine are completely melted to form transparent oily eutectic liquid. Putting polysorbate 80, lidocaine-prilocaine eutectic and a proper amount of purified water into a mixing container, stirring and homogenizing to emulsify the mixture to obtain O/W type emulsion.

Dissolving sodium polyacrylate NP-700 and polyvinyl alcohol in a prescription amount in purified water, fully mixing dihydroxyaluminium glycolate, propylene glycol, kaolin, glycerol and methyl p-hydroxybenzoate, adding the mixture into the purified water solution, and crosslinking to form a gel matrix. And then adding the O/W type emulsion into the gel matrix, and stirring and mixing uniformly to obtain a medicine-containing layer. And uniformly coating the medicine-containing layer on a polyethylene terephthalate (PET) film, and standing and forming. And (3) bonding the plaster with non-woven fabrics, and cutting the plaster into required sizes to obtain the lidocaine-prilocaine gel plaster.

Example 4: evaluation of local analgesic Effect

(1) Laboratory animal treatment

Male Kunming rats were fixed on a rat plate, abdominal rat hair was shaved off with an electric scissors, and a circumference of 2cm in diameter was fixed on abdominal skin. The electrodes were centered and the other electrode was varied at each quarter of the circumference. The output voltage of the physiological stimulator is adjusted, and the stimulation duration is 1 second. When the output voltage is 0, the hoarse sound is generated for 5 times continuously after 10 times of stimulation and the output voltage is 72V, and the person who is not called is discarded for 5 times continuously after 10 times of stimulation. And screening qualified rats for later use.

Fixing guinea pig on mouse board, and shaving off mouse hair of the median skin of back with an electric razor to obtain a length of about 10cm²Large and small areas, leaving the skin exposed. After shaving, the guinea pigs were left to rest for 24h to restore their back skin to a natural state.

(2) Classification of experimental groups

Blank control group (blank matrix, no drug administration); ② 2.5 percent lidocaine gel plaster group; ③ 2.5 percent prilocaine gel plaster group; fourthly, 5 percent lidocaine gel plaster group; 5% prilocaine gel plaster group; sixthly, 2.5 percent of lidocaine-2.5 percent of prilocaine gel plaster group (non-eutectic); seventhly, 2.5% lidocaine-2.5% prilocaine gel plaster group (Co-melting, example 3)

Note: each group included 6 guinea pigs except the blank control group (1).

(3) Dosing regimens and evaluation

The guinea pigs in the number required for the experimental group were divided into groups. Subsequently, each cut gel patch of the same size was applied to the skin in the exposed area, and the area was about 4cm². The pain response of a strip-shaped area with the width of about 6mm on the periphery of the skin area of the applied part is tested by acupuncture, and when the pain exists, the skin at the stimulation part has a contraction phenomenon. Each guinea pig was stimulated a total of 10 times at different points in the zonal zone and the number of negative responses to stimulation (i.e. no contraction of the skin on the back of the guinea pig after needling) was recorded. The test was performed once at 5, 10, 15, 20, 30, 40, 60, 80, 100, 120min after administration. The results are shown in the attached figures, the lidocaine-prilocaine gel plaster prepared in example 3 has fast effect and obviously better analgesic effect than other experimental groups. In addition, although the medicines used in the experimental group and the experimental group are all gel plasters of lidocaine-prilocaine medicine composition, the onset time and the analgesic effect of the latter are obviously superior to those of the former. The above results show that the unexpected effect can be obtained by the lidocaine-prilocaine eutectic form, and the drug effect is greatly improved compared with the single administration and the common combined administration.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. An external preparation of a pharmaceutical composition comprises lidocaine, prilocaine, a framework matrix material and pharmaceutically acceptable external preparation auxiliary materials, and is characterized in that the content of the lidocaine-prilocaine pharmaceutical composition in the external preparation is 1% -10%, wherein the lidocaine-prilocaine pharmaceutical composition exists in the external preparation as an oily eutectic substance.

2. The external preparation according to claim 1, wherein the external preparation is classified into a patch and a gel patch.

3. The external preparation as claimed in claims 1-2, wherein the lidocaine-prilocaine pharmaceutical composition is present in the patch as an oily eutectic and in the gel patch as an O/W type microemulsion.

4. The external preparation as claimed in claims 1-3, wherein the prescription composition of the patch comprises lidocaine, prilocaine, non-hydrophilic matrix material and pharmaceutically acceptable external preparation auxiliary material.

5. The external preparation according to claims 1 to 4, wherein the non-hydrophilic base material comprises a solvent-based base material and a hot-melt-type base material.

6. The external preparation as claimed in claims 1 to 5, wherein the prescription composition of the drug-containing layer of the patch includes but is not limited to:

1 to 10 percent of lidocaine

Prilocaine 1% -10%

Polyacrylate (DURO-TAK 180-129A) 10% -50%

5 to 15 percent of tocopherol

0 to 20 percent of kaolin

0.1 to 5 percent of propylene glycol

0.1 to 5 percent of methyl p-hydroxybenzoate.

7. The external preparation as claimed in claims 1 to 5, wherein the prescription composition of the drug-containing layer of the patch includes but is not limited to:

1 to 10 percent of lidocaine

Prilocaine 1% -10%

SIS D1163P 10%-50%

10 to 30 percent of terpene resin

20 to 30 percent of liquid paraffin

5 to 15 percent of butylated hydroxytoluene

0 to 20 percent of kaolin

0.1 to 5 percent of propylene glycol

0.1 to 5 percent of methyl p-hydroxybenzoate.

8. The external preparation according to claim 6, wherein the prescription composition of the drug-containing layer of the patch includes but is not limited to:

lidocaine 2.5%

Prilocaine 2.5%

Polyacrylate (DURO-TAK 180-129A) 50%

Tocopherol of 15%

20 percent of kaolin

Propylene glycol 5%

5 percent of methyl p-hydroxybenzoate.

9. The external preparation according to claim 7, wherein the prescription composition of the drug-containing layer of the patch includes but is not limited to:

lidocaine 2.5%

Prilocaine 2.5%

SIS D1163P 35%

Terpene resin 15%

20 percent of liquid paraffin

5 percent of dibutyl hydroxy toluene

Kaolin 10%

Propylene glycol 5%

5 percent of methyl p-hydroxybenzoate.

10. The external preparation as claimed in claims 1-3, wherein the formulation of the gel patch comprises lidocaine, prilocaine, emulsifier, hydrophilic gel matrix material and pharmaceutically acceptable external preparation auxiliary materials.

11. The external preparation as claimed in claims 1 to 3 and 10, wherein the prescription composition of the drug-containing layer of the gel patch includes but is not limited to:

1 to 10 percent of lidocaine

Prilocaine 1% -10%

Polysorbate-8010% -30%

Sodium polyacrylate NP-70010-50%

10 to 30 percent of polyvinyl alcohol

10 to 15 percent of glycerin

0.1 to 5 percent of propylene glycol

0 to 5 percent of dihydroxyaluminium aminoacetate

0 to 20 percent of kaolin

0.1 to 5 percent of methyl p-hydroxybenzoate

40-60% of purified water.

12. The external preparation as claimed in claim 11, wherein the prescription composition of the drug-containing layer of the gel patch includes but is not limited to:

lidocaine 2.5%

Prilocaine 2.5%

Polysorbate 807.5%

Sodium polyacrylate NP-70020%

Polyvinyl alcohol 10%

10 percent of glycerin

2.5 percent of propylene glycol

2.5 percent of dihydroxyaluminium aminoacetate

2.5 percent of methyl p-hydroxybenzoate

Purified water 40%.

13. The external preparation according to claims 1 to 12, which is useful for local superficial anesthesia or local pain relief.

14. The external preparation according to claim 13, which is useful for relieving local pain such as pain after injection, pain after puncture, pain due to intravenous indwelling needle, postherpetic neuralgia, and pain due to touch caused by herniated intervertebral disc.