WO2022100120A1 - External preparation of lidocaine-prilocaine pharmaceutical composition and application thereof - Google Patents

Abstract

An external preparation of a lidocaine-prilocaine pharmaceutical composition. The content of the lidocaine-prilocaine pharmaceutical composition is 1%-10%. The external preparation comprises a patch containing a lidocaine-prilocaine oily eutectic, a non-hydrophilic matrix material, and pharmaceutically acceptable external preparation auxiliary materials, and a gel patch containing a lidocaine-prilocaine O/W microemulsion, a hydrophilic gel matrix material, and pharmaceutically acceptable external preparation auxiliary materials. The patch and the gel patch can be used for local superficial anesthesia or relieving local pains such as post-injection pain, post-puncture pain, pain caused by a venous indwelling needle, postherpetic neuralgia, and touch pain caused by protrusion of intervertebral disc. The lidocaine-prilocaine eutectic is taken as an active ingredient, such that the percutaneous penetration rate and the absorption degree of lidocaine and prilocaine can be obviously improved, the beneficial effects of synergy are produced, and the occurrence rate of toxic and side effects of the lidocaine and the prilocaine is reduced.

Description

A kind of external preparation of lidocaine and 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 its application.

Background technique

Pain is a defining feature of many disease diagnoses and is an unpleasant sensation and experience. When the intensity of the external stimulus reaches the threshold, the nociceptive sensory fibers will be activated to generate nerve impulses, and the nerve impulses will be transmitted to the spinal cord and the center through afferent nerves to generate reflex responses and pain sensation. Common types of pain include protective pain, inflammatory pain, and neuropathic pain caused by acupuncture, high temperature, and extrusion. Pain, which can last for hours, days or even years, not only reduces the quality of life of patients, but also seriously affects their mental and physical health.

Pain relief methods mainly include oral analgesics and local injection of anesthetics to reduce the generation of nerve impulses or block the conduction of nerve impulses. However, oral administration has a long onset time and generally has strong gastrointestinal side effects or other adverse reactions, so it is not suitable for long-term medication. Local injection of anesthesia drugs must be operated by medical staff, which can easily lead to pain at the injection site and poor patient compliance. In addition, if the overdose of local anesthetics is used, the risk of systemic anesthesia, central toxicity and cardiotoxicity is greatly increased, and the safety is low. Therefore, although some examinations or surgeries have achieved local anesthesia or analgesia by applying local anesthetic drugs, the application space of this dosage form is limited due to the inaccurate dosage and the inability to continuously penetrate for a long time. The transdermal patch has the advantages of precise dose, non-invasive and painless administration, avoiding gastrointestinal side effects and first-pass effect, and reducing the frequency of administration, which improves the safety of administration and patient compliance.

At present, countries such as Europe and the United States have used the gel patch of the local anesthetic lidocaine as the first-line treatment for postherpetic neuralgia. Studies have shown that when lidocaine gel patch is transdermally administered, the release rate of the drug is slow, and the residual amount in the patch is large, resulting in a low utilization rate of active ingredients. In addition, the hepatic metabolites of lidocaine also have anesthetic and antiarrhythmic activities similar to the active ingredients. If used in excess, the risk of adverse reactions is greater. The combined use of lidocaine and other drugs can reduce the dosage of lidocaine, reduce the incidence of adverse reactions, and also achieve the purpose of synergism.

technical problem

Lidocaine-prilocaine pharmaceutical composition creams and gels are approved for superficial analgesia and oral local anesthesia. Prilocaine is similar to lidocaine, both of which are amide local anesthetics, both of which can block the generation and conduction of nerve impulses by blocking sodium ion channels and restricting the inflow of sodium ions, and exert local anesthesia or analgesia. effect. Lidocaine and prilocaine can form an oily eutectic in a certain proportion. Studies have shown that the transdermal penetration rate and absorption degree of the above eutectic are significantly increased compared with the use of the two alone, which can improve the efficacy of the two. And the combined use of the two reduces the usage of lidocaine and prilocaine, can reduce the incidence of adverse reactions and toxic side effects of the two, and improve the safety of administration. However, when the above-mentioned gels and creams are used, they cannot stay for a long time and are easily wiped off by clothes; if they are packaged, the operation is cumbersome. To sum up, the preparation of the current lidocaine-prilocaine pharmaceutical composition still has certain defects.

technical solutions

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

The technical solution of the present invention is as follows.

The invention provides an external preparation of a lidocaine-prilocaine pharmaceutical composition. The prescription comprises lidocaine, prilocaine, a skeleton matrix material and a pharmaceutically acceptable external preparation auxiliary material. The content of the in-prilocaine pharmaceutical composition in the external preparation is 1% - 10%. Among them, the lidocaine-prilocaine pharmaceutical composition exists as an oily eutectic.

The external preparations include patches and gel patches. Wherein, the lidocaine-prilocaine pharmaceutical composition exists in the patch as an oily eutectic; the lidocaine-prilocaine pharmaceutical composition exists in the gel patch as an O/W microemulsion.

The prescription composition of the said patch includes lidocaine, prilocaine, non-hydrophilic matrix material and pharmaceutically acceptable external preparation auxiliary materials, and the prescription composition of the said gel patch includes lidocaine, prilocaine, Emulsifier, hydrophilic gel matrix material and pharmaceutically acceptable external preparation excipients.

In the formulation composition of the external preparation, skeleton matrix materials are added, including hydrophilic gel matrix materials and non-hydrophilic matrix materials. Among them, the non-hydrophilic matrix materials include solvent-based, emulsion-based and hot-melt-based matrix materials.

Hydrophilic gel matrix materials include, but are not limited to, one of gelatin, gum arabic, polyacrylic acid with different degrees of polymerization and its sodium salt, sodium carboxymethyl cellulose, carbomer, polyvinyl alcohol, polyvinylpyrrolidone or variety.

Non-hydrophilic matrix materials include but are not limited to polyacrylates and their derivatives, styrene-isoprene-styrene block copolymers (SIS), polyisobutylenes and their derivatives, silicone rubber, silicone one or more of.

A pharmaceutically acceptable external preparation auxiliary material is added in the prescription composition of the external preparation, including but not limited to a thickener, a moisturizing agent, a skin penetration enhancer, an emulsifier, an antioxidant, a filler, and a preservative. or more.

The tackifier includes, but is not limited to, one or more of terpene resin, polystyrene propylene resin, and rosin resin.

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

Transdermal enhancers include, but are not limited to, one or more of propylene glycol, isopropyl myristate, isopropyl palmitate, menthol.

Emulsifiers include, but are not limited to, one or more of polysorbate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, glycerol monostearate, and phospholipids.

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, and silicic acid.

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

In the external preparation, the formulation composition of the drug-containing layer of the patch includes but is not limited to the following.

Lidocaine 1%-10%.

Prilocaine 1%-10%.

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

Tocopherol 5%-15%.

Kaolin 0%-20%.

Propylene glycol 0.1%-5%.

Methylparaben 0.1%-5%.

In the external preparation, the formulation composition of the drug-containing layer of the patch includes but is not limited to the following.

Lidocaine 1%-10%.

Prilocaine 1%-10%.

SIS D1163P 10%-50%.

Terpene resin 10%-30%.

Liquid paraffin 20%-30%.

Dibutylhydroxytoluene 5%-15%.

Kaolin 0%-20%.

Propylene glycol 0.1%-5%.

Methylparaben 0.1%-5%.

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

Lidocaine 1%-10%.

Prilocaine 1%-10%.

Polysorbate-80 10%-30%.

Sodium polyacrylate NP-700 10%-50%.

Polyvinyl alcohol 10%-30%.

Glycerin 10%-15%.

Propylene glycol 0.1%-5%.

Aluminum hydroxyaluminum 0%-5%.

Kaolin 0%-20%.

Methylparaben 0.1%-5%.

Purified water 40-60%.

The external preparation of the present invention can be used for local superficial anesthesia or local pain relief. Preferably, it can be used to relieve local pain such as pain after injection, pain after puncture, pain caused by intravenous indwelling needle, post-herpetic neuralgia, and tenderness caused by intervertebral disc herniation.

beneficial effect

The invention provides an external patch and a gel patch of the lidocaine-prilocaine pharmaceutical composition, which can be used for local superficial anesthesia or relieve local pain. The combined use of lidocaine and prilocaine can reduce the use of both, thereby reducing the incidence of toxic side effects. In addition, in the present invention, the pharmaceutical composition of lidocaine and prilocaine exists in the external preparation in the form of an oily eutectic, which can improve the transdermal penetration rate and absorption degree of the two, resulting in a synergistic effect. Based on the above, the external preparation of the lidocaine-prilocaine pharmaceutical composition provided by the present invention has good safety and high drug utilization rate, and provides a new choice for the analgesia and anesthesia needs of patients and medical staff.

Description of drawings

Figure 1. Changes of negative responses to acupuncture stimulation in each experimental group after administration.

Embodiments of the present invention

In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, the present invention can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific implementation disclosed below.

Unless otherwise defined, 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 terms used in the description of the present invention are for the purpose of describing specific embodiments only, and are not intended to limit the present invention.

Example 1: Lidocaine-prilocaine patch (solvent base).

The formulation composition is as follows.

component Proportion of prescriptions (%) effect Lidocaine 2.5 Active ingredient prilocaine 2.5 Active ingredient Polyacrylate (DURO-TAK 180-129A) 50 Solvent-based non-hydrophilic matrix Tocopherol 15 Antioxidants Kaolin 20 filler Propylene Glycol 5 skin penetration enhancer Methylparaben 5 preservative.

. Preparation technique: get the lidocaine and prilocaine of recipe quantity in container, be heated to 40-50 ℃, stir and mix until it melts completely, form transparent oily eutectic liquid. Take the recipe quantity DURO-TAK 180-129A, kaolin, tocopherol, propylene glycol, methylparaben and lidocaine-prilocaine oily eutectic into a mixing container, stir and mix evenly to obtain a drug-containing layer. The drug-containing layer is evenly coated on the polyethylene terephthalate PET film, and after laminating with the non-woven fabric, it is cut into the required size to obtain the lidocaine-prilocaine patch.

Example 2: Lidocaine-prilocaine patch (hot melt base).

The composition of the prescription is as follows: .

component Proportion of prescriptions (%) effect Lidocaine 2.5 Active ingredient prilocaine 2.5 Active ingredient SIS D1163P 35 Hot-melt non-hydrophilic matrix Terpene resin 15 Tackifier liquid paraffin 20 softener Dibutylhydroxytoluene 5 Antioxidants Kaolin 10 filler Propylene Glycol 5 skin penetration enhancer Methylparaben 5 preservative.

Preparation process: take lidocaine and prilocaine in prescription amounts into a container, heat to 40-50° C., stir and mix until they are completely melted, and form a transparent oily eutectic liquid. Take Prescription SIS D1163P, terpene resin, liquid paraffin, dibutyl hydroxytoluene, kaolin, propylene glycol and methyl parahydroxybenzoate were heated to 150°C to melt and mix uniformly. Subsequently, the lidocaine-prilocaine oily eutectic is added to the mixing container, and the mixture is stirred and mixed uniformly to obtain a drug-containing layer. The drug-containing layer is evenly coated on the polyethylene terephthalate PET film, and after laminating with the non-woven fabric, it is cut into the required size to obtain the lidocaine-prilocaine patch.

Example 3: Lidocaine-prilocaine gel patch.

The formulation composition is as follows.

component Proportion of prescriptions (%) effect Lidocaine 2.5 Active ingredient prilocaine 2.5 Active ingredient Polysorbate 80 7.5 Emulsifier Sodium Polyacrylate NP-700 20 hydrophilic matrix polyvinyl alcohol 10 hydrophilic matrix glycerin 10 moisturizer Propylene Glycol 2.5 skin penetration enhancer Aluminum Glycolate 2.5 cross-linking agent Methylparaben 2.5 preservative purified water 40 water box.

Preparation process: take lidocaine and prilocaine in prescription amounts into a container, heat to 40-50° C., stir and mix until they are completely melted, and form a transparent oily eutectic liquid. Polysorbate 80, lidocaine-prilocaine eutectic and an appropriate amount of purified water are placed in a mixing container, stirred and homogenized to emulsify to obtain an O/W emulsion.

Dissolve sodium polyacrylate NP-700 and polyvinyl alcohol in the prescribed amount in purified water, fully mix aluminum glycerol, propylene glycol, kaolin, glycerin, and methylparaben and add them to the above purified aqueous solution, and cross-link to form a coagulation. glue base. Then add the O/W type emulsion to the gel matrix, stir and mix evenly to obtain a drug-containing layer. The drug-containing layer is uniformly coated on the polyethylene terephthalate PET film, and it is allowed to stand to form. After laminating with the non-woven fabric, it is cut into the required size to obtain the lidocaine-prilocaine gel patch.

Example 4: Evaluation of local analgesic effect.

(1) Handling of experimental animals.

A male Kunming rat was taken and fixed on a rat board, the abdominal rat hair was shaved with electric scissors, and a circle with a diameter of 2 cm was fixed on the abdominal skin. The electrode is placed in the center and the other electrode is moved at each decibel of the circumference. Adjust the output voltage of the physiological stimulator, and the stimulation duration is 1 second. When the output voltage was 0, 10 times of stimulation, there were 5 consecutive hissing sounds and when the output voltage was 72V, those who did not call for 5 consecutive times after 10 stimulations were discarded. Qualified rats were screened out for use.

The guinea pig was fixed on the mouse plate, and the mouse hair in the middle of the back was shaved with an electric razor, and the skin was exposed in an area of about 10 cm ² . After shaving, the guinea pigs were placed to rest for 24 hours to restore their back skin to their natural state.

(2) Classification of experimental groups.

①Blank control group (blank matrix, no medication); ②2.5% lidocaine gel patch group; ③2.5% prilocaine gel patch group; ④5% lidocaine gel patch group; ⑤ 5% prilocaine gel patch group; ⑥ 2.5% lidocaine-2.5% prilocaine gel patch group (non-eutectic); ⑦ 2.5% lidocaine-2.5% prilocaine gel Patch group (eutectic, Example 3).

Note: Except for the blank control group (1), each other group included 6 guinea pigs.

(3) Dosing schedule and evaluation.

Take the required number of guinea pigs in the experimental group and group them. Subsequently, each gel patch, which has been cut out of the same size, is applied to the skin of the exposed area, with an area of about 4 cm ² . Acupuncture was used to test the pain response of a band-shaped area with a width of about 6 mm around the skin area of the medication part. Each guinea pig was stimulated for a total of 10 times at different points in the strip area each time, and the number of negative responses of each guinea pig to the stimulation (that is, no shrinkage of the skin on the back of the guinea pig after acupuncture) was recorded. After administration, test once at 5, 10, 15, 20, 30, 40, 60, 80, 100, 120 min respectively. The results are shown in Figure 1, the lidocaine-prilocaine gel patch prepared in Example 3 has a fast onset speed, and the analgesic effect is obviously better than other experimental groups. In addition, although the drugs used in both experimental group ⑥ and experimental group ⑦ were gel patches of lidocaine-prilocaine pharmaceutical composition, the onset time and analgesic effect of the latter were significantly better than those of the former. The above results show that, compared with single administration and common combined administration, administration in the form of lidocaine-prilocaine co-melt can obtain unexpected effects and greatly improve the efficacy.

The above-mentioned embodiments only represent several embodiments of the present invention, and the descriptions thereof are specific and detailed, but should not be construed as a limitation on the scope of the invention patent. It should be pointed out that for those skilled in the art, without departing from the concept of the present invention, several modifications and improvements can be made, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the appended claims.

Claims (14)

A kind of external preparation of pharmaceutical composition, the prescription composition comprises lidocaine, prilocaine, skeleton matrix material and pharmaceutically acceptable external preparation auxiliary material, it is characterized in that, lidocaine-prilocaine pharmaceutical composition is in external preparation The content of Lidocaine is 1%-10%; wherein, the lidocaine-prilocaine pharmaceutical composition is present in the external preparation as an oily eutectic. The external preparation according to claim 1, wherein the external preparation is divided into a patch and a gel patch. The external preparation according to claim 1-2, wherein the lidocaine-prilocaine pharmaceutical composition is present in the patch with oily eutectic, and is present in the gel patch with O/W type microemulsion middle. The external preparation according to claim 1-3, characterized in that, the prescription composition of the patch comprises lidocaine, prilocaine, non-hydrophilic matrix material and pharmaceutically acceptable external preparation auxiliary materials. The external preparation according to claims 1-4, wherein the non-hydrophilic matrix material comprises a solvent-based matrix material and a hot-melt matrix material. External preparation according to claim 1-5, is characterized in that, the prescription composition of patch drug-containing layer includes but is not limited to: lidocaine 1%-10%, Prilocaine 1%-10%, Polyacrylate (DURO-TAK 180-129A) 10%-50%, Tocopherol 5%-15%, Kaolin 0%-20%, Propylene glycol 0.1%-5%, Methylparaben 0.1%-5%. External preparation according to claim 1-5, is characterized in that, the prescription composition of patch drug-containing layer includes but is not limited to: lidocaine 1%-10%, Prilocaine 1%-10%, SIS D1163P 10%-50%, Terpene resin 10%-30%, Liquid paraffin 20%-30%, Dibutylhydroxytoluene 5%-15%, Kaolin 0%-20%, Propylene glycol 0.1%-5%, Methylparaben 0.1%-5%. External preparation according to claim 6, is characterized in that, the prescription composition of patch drug-containing layer includes but is not limited to: lidocaine 2.5%, Prilocaine 2.5%, Polyacrylate (DURO-TAK 180-129A) 50%, Tocopherol 15%, Kaolin 20%, Propylene Glycol 5%, Methylparaben 5%. External preparation according to claim 7, is characterized in that, the prescription composition of patch drug-containing layer includes but is not limited to: lidocaine 2.5%, Prilocaine 2.5%, SIS D1163P 35%, Terpene resin 15%, Liquid paraffin 20%, Dibutylhydroxytoluene 5%, Kaolin 10%, Propylene Glycol 5%, Methylparaben 5%. The external preparation according to claim 1-3 is characterized in that, the prescription composition of described gel patch comprises lidocaine, prilocaine, emulsifier, hydrophilic gel matrix material and pharmaceutically acceptable External preparation excipients. The external preparation according to claims 1-3 and 10, wherein the prescription composition of the medicated layer of the gel patch includes but is not limited to: Lidocaine 1%-10%, Prilocaine 1%-10%, Polysorbate-80 10%-30%, Sodium polyacrylate NP-700 10%-50%, Polyvinyl alcohol 10%-30%, Glycerin 10%-15%, Propylene glycol 0.1%-5%, Aluminum hydroxyaluminum 0%-5%, Kaolin 0%-20%, Methylparaben 0.1%-5%, Purified water 40-60%. The external preparation according to claim 11, wherein the prescription composition of the medicated layer of the gel patch includes but is not limited to: Lidocaine 2.5%, Prilocaine 2.5%, Polysorbate 80 7.5%, Sodium Polyacrylate NP-700 20%, Polyvinyl alcohol 10%, Glycerin 10%, Propylene Glycol 2.5%, Aluminium carboxylate 2.5%, Methylparaben 2.5%, Purified water 40%. The external preparation according to claims 1-12, characterized in that it can be used for local superficial anesthesia or local pain relief. The external preparation according to claim 13, characterized in that, it can be used for relieving local pains such as pain after injection, pain after puncture, pain caused by intravenous indwelling needle, postherpetic neuralgia, tenderness caused by intervertebral disc herniation.