CN115006533B

CN115006533B - Homogeneous phase aqueous composition containing local anesthetic

Info

Publication number: CN115006533B
Application number: CN202111629405.8A
Authority: CN
Inventors: 陈海靓; 杨意波; 石瑶丽; 李玲; 王青松
Original assignee: Nanjing Delova Biotech Co ltd
Current assignee: Nanjing Delova Biotech Co ltd
Priority date: 2021-12-28
Filing date: 2021-12-28
Publication date: 2023-07-14
Anticipated expiration: 2041-12-28
Also published as: CN115006533A

Abstract

The invention relates to a pharmaceutical composition comprising a pharmaceutically active ingredient, a pharmaceutically acceptable hydrogen bond donor and an aqueous matrix. The pharmaceutical composition is a homogeneous phase aqueous preparation, has the advantages of simple preparation process, good stability, quick response, extremely shortened waiting time of clinical patient administration, proper viscosity, quick drying and film forming after being smeared on skin, convenient clinical flexible dosage adjustment and administration, and simultaneously, the composition has small irritation and good administration safety and tolerance.

Description

Homogeneous phase aqueous composition containing local anesthetic

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a homogeneous phase aqueous composition containing local anesthetics, and a preparation method and application thereof.

Background

Lidocaine is an amide local anesthetic that blocks the generation and conduction of nerve impulses in excitable tissues by reducing or preventing the transient substantial increase in membrane permeability to sodium ions, producing pain relief. The lidocaine has the characteristics of strong penetrability, wide dispersion range, quick response, no irritation to skin, good safety and the like, thereby becoming one of the most commonly used local anesthetics in clinic. The conventional method of administration of the surface anesthetic is subcutaneous or intradermal injection, which is not only inconvenient but also daunting to the patient, and the local anesthetic is permeated into the body by transdermal administration to produce the anesthetic effect, which is a new trend of clinical superficial anesthetic administration at present.

At present, a plurality of external preparations of lidocaine are marketed at home and abroad. In 1992, lidocaine and prilocaine compound cream (2.5%/2.5%) was marketed in the united states under the trade name of

Can be used for relieving pain during venipuncture. However, the medicine has slow effect, about 60 minutes is needed, and the medicine needs to be covered and sealed by an adhesive tape in the using process, so that the compliance of the patient on the medicine is poor. In addition, metabolites of the compound prilocaine in the body may cause methemoglobin symptoms, thereby compromising the oxygen carrying capacity of iron, thus limiting its use to some extent. In 1994, 60% lidocaine tape patch was marketed in Japan under the trade name +.>

Is used for relieving pain during the puncture of the indwelling needle. However, the medicine has slow onset time, about 30 minutes, and the production process of the patch is complex, which is not beneficial to dosage adjustment during medicine application. In 2006, lidocaine and tetracaine compound cream (7%/7%) was marketed in the united states, and a quick-acting anesthetic for pre-operative administration of skin was developed with the use of lidocaine and tetracaine in a low eutectic state at room temperature in a liquid state, with a time period of 20 minutes. However, the compound component tetracaine contains ester groups, is easy to hydrolyze, the preparation needs to be stored at 2-8 ℃, and the cream is a thermodynamically unstable multiphase system, so that the risk of demulsification and delamination exists.

Patent CN101816642B discloses a compound lidocaine and prilocaine cream and a preparation method thereof, and the production cycle generally requires 2 working days, carbomer needs to be soaked one day in advance, and the production efficiency is low. In the process, 8% -40% sodium hydroxide solution is added, and the mixture is stirred vigorously for 10-20 minutes, so that the pH value of the mixture reaches more than 9. Whether factors such as adding speed, stirring speed, time control, personnel and the like are properly operated or not directly influences the viscosity value of the mixed solution, the viscosity or the high or low viscosity can influence the emulsification effect and the permeability of the product, the process control is difficult, and the stability of the product is influenced.

Patent CN101861148B discloses a non-aqueous tape formulation containing more than 10% lidocaine, which uses equimolar lidocaine lactate to prepare a high-concentration lidocaine formulation, which is better in percutaneous absorption than Penles patches. However, on one hand, the production and use of the patch have limitations, and on the other hand, the system is an oil-phase system, which is not beneficial to transdermal absorption of the drug. Furthermore, experiments have shown that equimolar lidocaine lactate does not significantly improve the solubility of lidocaine in water.

Patent US005919479a discloses a device, product formulation and method for improving skin penetration of a drug, the formulation being a compound lidocaine and tetracaine cream, the patent introducing two mechanisms of active drug entry into the skin in an oil-in-water emulsion formulation, the first being oil droplets contacting the skin and delivering the drug to the skin. The second is that the dissolved drug in the aqueous phase contacts and penetrates the skin. For cream formulations where the oil phase is a local anesthetic low co-melt, most of the active drug is present in the oil phase. The first mechanism is therefore considered to be dominant. However, the experimental results indicate that the effective time is determined by the skin absorption of the drug (especially tetracaine) dissolved in the aqueous phase, although this is only a small fraction of the total amount of drug in the formulation.

In view of the above-mentioned problems in the prior art, there is an urgent need to develop a homogeneous aqueous formulation for transdermal local anesthesia, which has a high drug loading rate, has a rapid onset of action, and does not have to be administered by injection.

Disclosure of Invention

In order to solve the technical problems, the invention provides a pharmaceutical composition, which comprises the following components:

a. a pharmaceutically active ingredient;

b. a pharmaceutically acceptable hydrogen bond donor, which is a compound containing-COOH or-OH;

c. an aqueous matrix;

according to embodiments of the present invention, the pharmaceutical composition may optionally further comprise d. a pharmaceutically acceptable penetration enhancer.

According to embodiments of the present invention, the pharmaceutical composition may optionally further comprise e. a pharmaceutically acceptable fragrance.

According to an embodiment of the present invention, the pharmaceutical composition may optionally further comprise a f.

According to embodiments of the present invention, the pharmaceutical composition may optionally further comprise a g.ph adjuster.

According to an embodiment of the present invention, the a-component pharmaceutically active ingredient is not limited to a therapeutic type, and may be one or more of an anti-inflammatory agent, local anesthetic, analgesic, antipsychotic, anxiolytic, sedative-hypnotic, antidepressant, antihypertensive, steroid hormone, antiepileptic, bactericidal, anticonvulsant, anti-parkinsonism, central nervous stimulant, antipsychotic, antiarrhythmic, anti-angina pectoris, antithyroid, antidote, antiemetic, hypoglycemic, antituberculosis, anti-aids, anti-hepatitis b, antineoplastic, anti-rejection.

According to an embodiment of the invention, the a-component active agent is selected from amide local anesthetics, for example from bupivacaine, ropivacaine, prilocaine, lidocaine, tetracaine or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt is selected from hydrochloride, mesylate, sulfonate, phosphate, acetate, citrate, maleate and the like.

According to an embodiment of the invention, the b-component is a pharmaceutically acceptable hydrogen bond donor selected from one or more of organic acids, amino acids and polyols. The organic acid comprises one or more of acetic acid, propionic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, citric acid, sorbic acid, malic acid, caprylic acid, caproic acid, butyric acid, adipic acid, valeric acid, heptanoic acid, capric acid, oleic acid, linoleic acid, lauric acid, palmitic acid, lactic acid, benzoic acid and gentisic acid; the amino acids include glutamic acid, aspartic acid; the polyalcohol comprises one or more of ethylene glycol, glycerol, sorbitol, glucose, sucrose, trehalose, rhamnose, propylene glycol and mannitol.

According to an embodiment of the invention, the aqueous matrix of component c is selected from one or more of polyvinyl alcohol, carbomer, sodium carboxymethylcellulose, polyoxyethylene pyrrolidone, hydroxypropyl methylcellulose.

According to an embodiment of the invention, the pharmaceutically acceptable permeation enhancer of component d is selected from one or more of sulfoxides, pyrrolones, laurocapram (Azone) and analogues thereof, fatty acids and esters thereof, surfactants, alcohols, polyols, terpenes, amines and amides, phospholipids, saccharides, amino acids and esters thereof, macrocyclic compounds, organic solvents.

The sulfoxides mainly comprise dimethyl sulfoxide, decyl methyl sulfoxide and the like. The pyrrolones mainly include 2-pyrrolidone, 1-methyl-2-pyrrolidone (NMP), 5-methyl-2-pyrrolidone, l, 5-methyl-2-pyrrolidone, 1-ethyl-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, etc. The laurocapram (Azone) and analogues thereof are Azone. The fatty acid and the esters thereof mainly comprise oleic acid, linoleic acid, lauric acid and esters thereof, isopropyl myristate, propylene glycol dipelargonate and diethyl sebacate. The surfactant can be nonionic, cationic and anionic surfactants, including caprylic capric polyethylene glycol glyceride, propylene glycol monocaprylate, etc. The alcohols mainly comprise ethanol, butanol, n-heptanol, n-octanol and the like. The polyalcohol mainly comprises propylene glycol, glycerol and the like. The terpenes mainly comprise eucalyptol, peppermint oil, nerolidol and the like. The amine and amide are mainly urea, dodecyl-N, N-dimethylaminoethyl ester, dimethylformamide, dimethylacetamide and the like. The phospholipids mainly comprise lecithin, soybean lecithin, phosphatidylglycerol, phosphatidylethanolamine, etc. The saccharide mainly comprises cyclodextrin, 2-hydroxypropyl-cyclodextrin, etc. The amino acid and the esters thereof mainly comprise L-isoleucine and dodecyl pyroglutamate. The macrocyclic compounds mainly comprise pentadecanone. The organic solvents mainly comprise ethyl acetate, diethylene glycol monoethyl ether and the like.

According to an embodiment of the invention, the pharmaceutically acceptable flavoring agent of component e is selected from one or more of borneol, orange peel syrup, cinnamon syrup, glycerin, sorbitol, mannitol, stevia, erythritol, saccharin or a salt thereof, cyclamate, xylitol, aspartame, fructose, sucralose, lemon, peppermint essential oil, menthol, apple essence, banana essence, strawberry essence, acesulfame potassium, nitrous acid amide, asparagine-acesulfame potassium, cyclamic acid or a salt thereof.

According to an embodiment of the invention, the solvent of component f is selected from water, alcohols selected from one or more of methanol, ethanol, ethylene glycol, propylene glycol, t-butanol or mixtures thereof.

According to an embodiment of the present invention, the pH adjuster of the g component comprises a basic pH adjuster selected from one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, diethanolamine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, tris (hydroxymethyl aminomethane), arginine, lysine, histidine and glycine, and an acidic pH adjuster; the acidity regulator is one or more selected from vitamin C (also called ascorbic acid), lactic acid, malic acid, fumaric acid, citric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid and acetic acid.

According to an embodiment of the invention, the pharmaceutically active ingredient comprises 0.1% to 61.0% (w/w) of the total composition. In some embodiments, the pharmaceutically active ingredient comprises 3% (w/w) to 61% (w/w) of the total composition, preferably, the pharmaceutically active ingredient comprises 5% (w/w) to 35% (w/w) of the total composition. For example, from 5%,6%,7%,8%,9%,10%,11%,12%,13%,14%,15%,16%,17%,18%,19%,20%,21%,22%,23%,24%,25%,26%,27%,28%,29%,30%,31%,32%,33%,34%,35%.

According to an embodiment of the invention, the molar ratio of the hydrogen bond donor to the pharmaceutically active ingredient is from 0.01:1 to 50:1, preferably the molar ratio of the hydrogen bond donor to the pharmaceutically active ingredient is from 50:1 to 1:50. In some embodiments, the molar ratio of hydrogen bond donor to pharmaceutically active ingredient is from 10:1 to 1:10. For example, the molar ratio is selected from 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10.

According to an embodiment of the invention, the hydrogen bond donor comprises 0.1% to 50% (w/w) of the total composition. According to some embodiments, the hydrogen bond donor comprises 0.1% to 31% (w/w) of the total composition, e.g., 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%, 13.0%, 13.5%, 14.0%, 14.5%, 15.0%, 15.5%, 16%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, 20%, 20.5%, 21.5%, 22.5%, 23.5%, 24.5%, 25.5%, 30%,31% (w/w).

According to an embodiment of the invention, the aqueous base comprises 0% to 18% (w/w) of the total composition, preferably 0.1% to 12% (w/w) of the total composition. For example, 1%,2%,3%,4%,5%,6%,7%,8%,9%,10%,11%,12% (w/w).

According to an embodiment of the invention, the penetration enhancer comprises 0% to 40% (w/w) of the total composition, preferably 1% to 20% (w/w) of the total composition. For example, 1%,2%,3%,4%,5%,6%,7%,8%,9%,10%,11%,12%,13%,14%,15%,16%,17%,18%,19%,20% (w/w).

According to an embodiment of the invention, the fragrance comprises from 0% to 5% (w/w), preferably from 0.1% to 1.0% (w/w), of the total composition. For example, 0.1%,0.2%,0.3%,0.4%,0.5%,0.6%,0.7%,0.8%,0.9%,1.0% (w/w).

According to an embodiment of the invention, the solvent comprises from 10% to 95% (w/w), preferably from 25% to 79% (w/w), for example from 25%,26%,27%,28%,29%,30%,31%,32%,33%,34%,35%,36%,37%,38%,39%,40%,41%,42%,43%,44%,45%,46%,47%,48%,49%,50%,51%,52%,53%,54%,55%,56%,57%,58%,59%,60%,61%,62%,63%,64%,65%,66%,67%,68%,69%,70%,71%,72%,73%,74%,75%,76%,77%,78%,79% w/w; in some embodiments, when the solvent is selected from a mixture of water and alcohol, the mass ratio of water to alcohol is from 1:1 to 5:1, for example 1:1,2:1,3:1,4:1,5:1.

According to an embodiment of the invention, the pH of the composition may range from 1.0 to 10.0, more preferably from 2.0 to 7.0, for example selected from 2.0,2.5,3.0,3.5,4.0,4.5,5.0,5.5,6.0,6.5,7.0.

According to embodiments of the present invention, in some embodiments, the pharmaceutically acceptable hydrogen bond donor forms a complex with the pharmaceutically active ingredient, the complex being in liquid form at 20-100 ℃, preferably, the complex is in liquid form at room temperature; in some embodiments, the pharmaceutically acceptable hydrogen bond donor forms a complex with the pharmaceutically active ingredient moiety.

In a second aspect, the invention provides complexes formed by the pharmaceutically acceptable hydrogen bond donors and pharmaceutically active ingredients.

In a third aspect, the invention provides a pharmaceutical composition comprising a complex formed by the pharmaceutically acceptable hydrogen bond donor and a pharmaceutically active ingredient. The pharmaceutical composition may further comprise one or more of the a-component, the b-component, the c-component, the d-component, the e-component, the f-component and the g-component. The content of the component a, the component b, the component c, the component d, the component e, the component f and the component g in the composition is defined as above; in the complex, the molar ratio of the hydrogen bond donor to the pharmaceutically active ingredient is 50:1 to 1:50. In some embodiments, the molar ratio of hydrogen bond donor to pharmaceutically active ingredient is from 10:1 to 1:10. For example, the molar ratio is selected from 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10.

The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: mixing the pharmaceutically active ingredients, pharmaceutically acceptable hydrogen bond donors. Further, the mixing step further comprises adding one or more of an aqueous base, a pharmaceutically acceptable penetration enhancer, a fragrance, a solvent and a pH regulator. The mixing comprises the steps of heating and stirring in the field to ensure that the solution is fully and uniformly mixed.

In some embodiments, the method of preparing the pharmaceutical composition comprises the steps of:

(a1) Mixing the pharmaceutically active ingredient and the pharmaceutically acceptable hydrogen bond donor, and stirring under heating to obtain clear mixed liquid;

(a2) Mixing an aqueous matrix with the liquid obtained in step (a 1);

according to an embodiment of the invention, the preparation method optionally comprises the steps of:

(a 2-1) mixing the aqueous substrate with a solvent to prepare a solution of the aqueous substrate, and mixing the aqueous substrate solution with the liquid obtained in the step (a 1).

(a3) Stirring and mixing pharmaceutically acceptable permeation enhancer and/or aromatic agent and solvent, mixing and stirring with the solution obtained in step (a 2) or (a 2-1) to homogeneous phase, and cooling to room temperature.

(a4) Adding a proper amount of pH regulator into the solution obtained in the step (a 2) or (a 2-1) or (a 3), and stirring until the mixture is uniform.

In a further aspect, the present invention provides an external preparation comprising a pharmaceutical composition as defined hereinbefore (including the pharmaceutical compositions of the first, second and third aspects), which preparation can be administered topically. The external preparation can be cream, patch, gel, film coating agent, liniment, emplastrum and the like.

Terms and abbreviations

Abbreviations used in the present invention have the following definitions: HBD is hydrogen bond donor, CMC-Na is sodium carboxymethyl cellulose, PVA-17-88 is polyvinyl alcohol;

is caprylic acid capric acid polyethylene glycol glyceride; />

P is diethylene glycol monoethyl ether; IPM is isopropyl myristate; CAPRYOL ^TM 90 is propylene glycol monocaprylate.

Advantageous effects

1) The invention surprisingly discovers that the specific water-soluble compound formed by the caine local anesthetics is beneficial to preparing the aqueous preparation with high concentration of active ingredients, and simultaneously meets the requirement that the active ingredients exert good transdermal absorption performance in the aqueous preparation.

2) The composition has the advantages that the local anesthetic component has a high drug-loading range, and compared with other external preparations sold in the market, the composition has quicker effect and shortens the waiting time of clinical patient medication;

3) The composition is a homogeneous phase aqueous preparation, and has simple preparation process and good stability;

4) The composition has proper viscosity, can be quickly dried to form a film after being smeared on skin, and is convenient for clinical flexible dosage adjustment and administration;

5) The composition has small irritation and good medication safety and tolerance.

Drawings

FIG. 1 shows the dissolution of lidocaine in medium of different pH (100 mg/ml)

FIG. 2 is a schematic representation of the dissolution of lidocaine and benzoic acid complex in medium of different pH (328.6 mg/ml)

FIG. 3 is a graph showing the results of in vitro release of formulations of different drug loading rates in aqueous media

FIG. 4 illustrates the in vitro release results of composition 1030 and commercially available formulations

FIG. 5 illustrates the in vitro transdermal results of composition 1030 and the commercially available formulation Pliaglis

FIG. 6 illustrates the in vitro transdermal results of composition 1030 and commercially available formulation EMLA

FIG. 7 is a schematic view showing the needling site of a guinea pig skin needling model

FIG. 8 is a graph showing analgesic effect of administration in a guinea pig skin acupuncture model, i.e., a guinea pig muscle contraction as an index

FIG. 9 is a graph showing the analgesic effect of administration in a guinea pig skin acupuncture model, namely, the cavy cry as an index

Detailed Description

The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.

Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.

Example 1

Complex system research of local anesthetics and HBD

Different types of HBD and local anesthetics were mixed in a molar ratio according to Table 1, heated to complete melting, and observed for appearance changes after standing overnight at room temperature.

TABLE 1 Complex object System study of local anesthetics and HBD

Example 2

Research on dissolution of local anesthetic-HBD complex in water

The HBD and local anesthetic are prepared into a compound according to a certain molar ratio, purified water is added, and the compound is shaken to observe the dissolution condition.

TABLE 2-1 dissolution of local anesthetic-HBD Complex in Water at equal mass ratio

TABLE 2 dissolution of local anesthetic-HBD complexes in Water at different Mass ratios

Wherein ∈r represents that the solution is possible and x represents that the solution is impossible.

As shown by the results, a part of the HBD and the local anesthetics of different types form complexes which have better solubility in water, and some complexes and water can be mutually dissolved in different proportions.

Example 3

Dissolution of local anesthetics and their complexes in different pH media

pH1.0 Medium: 9mL of concentrated hydrochloric acid is measured and placed in 1L of purified water, and the mixture is uniformly mixed.

pH2.0 Medium: 1.17mL of concentrated hydrochloric acid is measured and placed in 1L of purified water, and the mixture is uniformly mixed.

pH3.0 Medium: 4.9g of phosphoric acid is weighed and placed in 1L of purified water, evenly mixed, and NaOH is added to adjust the pH to 3.0.

pH4.0 Medium: 9.6g of anhydrous citric acid is weighed and placed in 1L of purified water, stirred and dissolved, and NaOH is added to regulate the pH value to 4.0.

pH5.0 Medium: 9.6g of anhydrous citric acid is weighed and placed in 1L of purified water, stirred and dissolved, and NaOH is added to regulate the pH value to 5.0.

pH6.0 Medium: 0.6g of anhydrous sodium dihydrogen phosphate is weighed and placed in 1L of purified water, stirred and dissolved, and NaOH is added to regulate the pH value to 6.0.

ph7.0 medium: 0.6g of anhydrous sodium dihydrogen phosphate is weighed and placed in 1L of purified water, stirred and dissolved, and NaOH is added to regulate the pH value to 7.0.

pH8.0 Medium: 0.6g of anhydrous sodium dihydrogen phosphate is weighed and placed in 1L of purified water, stirred and dissolved, and NaOH is added to regulate the pH value to 8.0.

pH9.0 Medium: 5.3g of anhydrous sodium carbonate is weighed and placed in 1L of purified water, stirred and dissolved, and concentrated hydrochloric acid is added to adjust the pH to 9.0.

pH10.0 Medium: 5.3g of anhydrous sodium carbonate is weighed and placed in 1L of purified water, stirred and dissolved, and concentrated hydrochloric acid is added to adjust the pH to 10.0.

A suitable amount of local anesthetic was added to the medium according to table 3, sonicated, and observed for dissolution of local anesthetic in different pH media. Making equimolar local anesthetic and HBD into a compound, adding a medium with the same mass ratio as the compound, shaking, and observing the dissolution condition.

TABLE 3 dissolution of local anesthetics in different pH Medium

FIGS. 1 and 2 are solutions of lidocaine (100 mg/mL) and lidocaine-benzoic acid complex (328.6 mg/mL), respectively, in different pH media. By examining the dissolution of the local anesthetic and the local anesthetic-HBD complex in different pH media, it was unexpectedly found that the solubility of the local anesthetic-HBD complex in different pH media was significantly improved after formation of the complex.

Example 4

Carbomer gel System study

The local anesthetic-HBD-carbomer composition was prepared as shown in Table 4, and the precipitation of local anesthetics was observed.

The preparation method comprises the following steps:

1) 4% (wt%) carbomer: and (3) scattering a proper amount of carbomer on the water surface overnight, standing for swelling, and then dripping triethanolamine to adjust the pH to be more than 6.

2) Heating and stirring local anesthetic and HBD into liquid, adding carbomer with prescribed amount, supplementing water, and stirring.

TABLE 4 local anesthetic-HBD-carbomer compositions

Example 5

Research on polyvinyl alcohol system

The local anesthetic-HBD-polyvinyl alcohol composition was prepared as shown in Table 5, and the precipitation of local anesthetics was observed.

The preparation method comprises the following steps:

1) PVA 17-88 solution: adding a proper amount of PVA 17-88 into water while stirring, and stirring until the PVA is completely swelled. Heating to 90 deg.C, stirring and dissolving.

2) Heating and stirring local anesthetic and HBD into liquid, adding PVA 17-88 with prescribed amount, supplementing water, and stirring uniformly.

TABLE 5 local anesthetic-HBD-polyvinyl alcohol compositions

Example 6

Local anesthetic-HBD-aqueous System study

The local anesthetic-HBD-aqueous matrix composition was prepared as shown in Table 6, and the precipitation of local anesthetics was observed.

TABLE 6 Lidocaine-HBD-aqueous base composition

Example 7

Local anesthetic-HBD-permeation enhancer aqueous system research

Different types of local anesthetics-HBD-permeation enhancer aqueous system compositions are prepared according to the table 7, and the precipitation condition of the local anesthetics is observed.

TABLE 7 Lidocaine-HBD-permeation enhancer aqueous system compositions

Example 8

Local anesthetic-HBD-fragrance aqueous System study

Different types of local anesthetics-HBD-fragrance aqueous system compositions were prepared according to Table 8, and the precipitation of local anesthetics was observed.

Table 8 local anesthetic-HBD-fragrance aqueous system compositions

Example 9

Preparation of samples at different pH for examination, samples were prepared according to Table 9-1, pH was adjusted with 10M sodium hydroxide solution and 10M hydrochloric acid solution, and the property change of the samples was observed.

TABLE 9-1 Lidocaine-HBD-polyvinyl alcohol compositions

TABLE 9-2 Lidocaine-HBD-polyvinyl alcohol compositions samples at different pH' s

pH	PH regulator	Phenomenon (1)
			0.63	10M hydrochloric acid	Transparent viscous liquid
3.80	10M hydrochloric acid	Transparent viscous liquid
			5.27	10M hydrochloric acid	Transparent viscous liquid
5.87	10M hydrochloric acid	Transparent viscous liquid
			6.16	10M hydrochloric acid	Transparent viscous liquid
6.71	Initial pH	Transparent viscous liquid
			6.92	10M sodium hydroxide	Transparent viscous liquid
7.03	10M sodium hydroxide	Transparent viscous liquid
			7.29	10M sodium hydroxide	Turbid viscous liquid

Example 10

In vitro release of local anesthetic-HBD-polyvinyl alcohol compositions

Different pharmaceutical compositions were prepared as in table 10-1 and release in water was measured using Franz diffusion Chi Fa. The polymer film was polyethersulfone (0.45 μm 25 mm), the speed of rotation was 200rpm, the test temperature was 32 ℃, the dosage of the

compositions

1029, 1030, 1031 was 300mg, the dosage of the

compositions

1032, 1033 was 150mg, samples were taken at 0.25, 0.5, 0.75, 1,2 and 3 hours, respectively, and immediately supplemented with the same temperature, the same volume of medium, and three runs were run in parallel for each set of experiments. The results are shown in Table 10-2 and FIG. 3.

TABLE 10-1 local anesthetic-HBD-polyvinyl alcohol compositions

TABLE 10-2 in vitro Release of local anesthetic-HBD-polyvinyl alcohol compositions

From the above results, it can be seen that the local anesthetic-HBD formulation released better than the local anesthetic alone (comparisons 1032 and 1033), and that the lidocaine release increased as the drug loading in the formulation increased (

comparisons

1029, 1030, 1031).

Example 11

In vitro release of local anesthetic-HBD-polyvinyl alcohol compositions and commercially available formulations

Pharmaceutical compositions were prepared as in Table 11-1 and tested by Franz diffusion cell method for release of the commercial formulations EMLA cream and Pliaglis cream in 30% ethanol. The polymer film was polyethersulfone (0.45 μm 25 mm), the rotation speed was 200rpm, the test temperature was 32℃and the dosage was 300mg, 0.3mL was sampled at 0.25, 0.5, 0.75, 1,2 and 3h, respectively, and the same temperature, the same volume of medium was immediately replenished. The release results are shown in Table 11-2 and FIG. 4.

TABLE 11-1 local anesthetic-HBD-polyvinyl alcohol composition

TABLE 11-2 in vitro Release results of pharmaceutical compositions, EMLA and Pliaglis

Example 12

Local anesthetic-HBD-polyvinyl alcohol composition and in-vitro transdermal preparation of commercial preparation

Comparison of in vitro transdermal rates of composition 1030 and Pliaglis:

the penetration of composition 1030 and the commercially available formulation Pliaglis cream in normal saline was determined using the Franz diffusion cell method. The isolated skin is pigskin, the rotating speed is 200rpm, the test temperature is 32 ℃, the dosage is 300mg, 1mL is sampled at 0.5, 1, 1.5, 2, 2.5,3, 4, 5 and 6 hours respectively, the same temperature and the same volume of medium are immediately supplemented, and four times of test are operated in parallel.

The in vitro transdermal results are shown in Table 12-1 and FIG. 5 below:

table 12-1 pharmaceutical composition and in vitro transdermal results of Pliaglis

In vitro transdermal rate comparison of composition 1030 and EMLA:

the penetration of composition 1030 and commercially available formulation EMLA cream in normal saline was determined using the Franz diffusion cell method. The isolated skin is pigskin, the rotating speed is 200rpm, the test temperature is 32 ℃, the dosage is 300mg, 1mL is sampled at 0.5, 1, 1.5, 2, 2.5,3, 4, 5 and 6 hours respectively, the same temperature and the same volume of medium are immediately supplemented, and four times of test are operated in parallel.

The in vitro transdermal results are shown in Table 12-2 and FIG. 6 below:

table 12-2 pharmaceutical composition and in vitro transdermal results of EMLA

Example 13

Pharmacodynamics study of pharmaceutical compositions were prepared as shown in table 13-1 below.

TABLE 13-1 local anesthetic-HBD-polyvinyl alcohol compositions

Composition numbering	1034
		Lidocaine	25.0
Benzoic acid	13.0
		Polyvinyl alcohol 17-88	10
Ethanol	19.9
		Menthol	0.1
Purified water	32.0

The drug effect of the pharmaceutical composition 1034 and the commercially available preparations of EMLA cream and Pliaglis cream were investigated by establishing a simple and reliable guinea pig skin acupuncture model, and the drug effect of the three preparations at different administration times was investigated.

Dosing regimen 1: 1034. EMLA, pliaglis all are administered for 15min;

dosing regimen 2: 1034. EMLA, pliaglis all were dosed for 30min;

dosing regimen 2: 1034. EMLA, pliaglis all are administered for 60min;

the hairless treatment is carried out on guinea pigs in advance for 24 hours, the back of the guinea pigs takes the backbone as a central line, a square administration area of 2x2 cm is drawn on the administration area on one side of the backbone, about 0.3g of the administration area is smeared by using a 1ml syringe, the medicine (EMLA) is firstly wiped off or the medicine film (1034 and Pliaglis) is torn off by using a dry paper towel after 15/30/60min of the administration, and then the medicine film is wiped once again by using a 75% alcohol cotton ball.

TABLE 13-2 needle punch time Point design

The needling method comprises the following steps: in each needling, the skin of the blank non-administration area is firstly needled to enable the guinea pig to have pain response (cry and skin contraction) feedback, and then the administration part is needled.

The number of needle sticks and the time: the back is needled 6 times at each time point (needling is continued for the next point without the need for repeated needling at that point after needling at each point without the need for whisking or muscle contraction feedback), with two needling intervals of 3-5s (see fig. 7 for a schematic of the needling site). The results of guinea pig needle punching are shown in FIGS. 8-9.

The above description has been given of exemplary embodiments of the present invention. However, the scope of the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A pharmaceutical composition comprising the following components:

a. a pharmaceutically active ingredient selected from bupivacaine, ropivacaine, prilocaine, lidocaine, tetracaine or a pharmaceutically acceptable salt thereof; the pharmaceutically active ingredient comprises 0.1% to 61.0% (w/w) of the total composition;

b. a pharmaceutically acceptable hydrogen bond donor selected from one or more of acetic acid, propionic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, citric acid, sorbic acid, malic acid, caprylic acid, caproic acid, butyric acid, adipic acid, valeric acid, enanthic acid, capric acid, oleic acid, linoleic acid, lauric acid, palmitic acid, lactic acid, benzoic acid, gentisic acid; the hydrogen bond donor comprises 0.1% to 50% (w/w) of the total composition;

c. an aqueous matrix selected from one or more of polyvinyl alcohol, carbomer, sodium carboxymethylcellulose, polyoxyethylene pyrrolidone, hydroxypropyl methylcellulose; the aqueous base comprises 0.1% to 18% (w/w) of the total composition;

the pharmaceutically acceptable hydrogen bond donor forms a complex with the pharmaceutically active ingredient.

2. The pharmaceutical composition of claim 1, further comprising f. a solvent selected from the group consisting of water, alcohols selected from one or more of methanol, ethanol, ethylene glycol, propylene glycol, t-butanol, or mixtures thereof.

3. The pharmaceutical composition according to claim 2, wherein when the solvent is selected from the group consisting of a mixture of water and an alcohol, the mass ratio of water to alcohol is 1:1 to 5:1.

4. The pharmaceutical composition of claim 1, further comprising d. a pharmaceutically acceptable permeation enhancer selected from one or more of sulfoxides, pyrrolones, laurocapram and analogs thereof, surfactants, alcohols, polyols, terpenes, amines and amides, sugars, amino acids and esters thereof, macrocyclic compounds, organic solvents.

5. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, mesylate, sulfonate, phosphate, acetate, citrate, maleate.

6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises e. a pharmaceutically acceptable fragrance; the pharmaceutically acceptable flavoring agent is selected from one or more of borneol, orange peel syrup, cinnamon syrup, glycerol, sorbitol, mannitol, stevia, erythritol, saccharin or salt thereof, sodium cyclamate, xylitol, aspartame, fructose, sucralose, lemon, peppermint volatile oil, menthol, apple essence, banana essence, strawberry essence, potassium acetate sultone, diazonium acid amide, asparagine-acetate sultone, cyclamate or salt thereof.

7. The pharmaceutical composition of claim 1, further comprising a g.ph adjuster comprising a basic pH adjuster selected from one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, diethanolamine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, tris, arginine, lysine, histidine and glycine and an acidic pH adjuster; the acidity regulator is one or more selected from ascorbic acid, lactic acid, malic acid, fumaric acid, citric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid and acetic acid.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutically active ingredient comprises 3% (w/w) to 61% (w/w) of the total composition.

9. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutically active ingredient is 5% (w/w) to 35% (w/w) of the total composition.

10. The pharmaceutical composition according to any one of claims 1-7, wherein the hydrogen bond donor comprises 0.1% to 31% (w/w) of the total composition.

11. The pharmaceutical composition according to any one of claims 1-7, wherein the aqueous matrix comprises 0.1% to 12% (w/w) of the total composition.

12. The pharmaceutical composition according to claim 2, wherein the solvent comprises 10% to 95% (w/w) of the total composition.

13. The pharmaceutical composition according to claim 2, wherein the solvent comprises 25% to 79% (w/w) of the total composition.

14. The pharmaceutical composition according to claim 4, wherein the penetration enhancer comprises 0% to 40% (w/w) of the total composition.

15. The pharmaceutical composition according to claim 4, wherein the penetration enhancer comprises 1% to 20% (w/w) of the total composition.

16. The pharmaceutical composition according to claim 6, wherein the fragrance comprises 0% to 5% (w/w) of the total composition.

17. The pharmaceutical composition according to claim 6, wherein the fragrance comprises 0.1% to 1.0% (w/w) of the total composition.

18. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pH of the composition is in the range of 1.0 to 10.0.

19. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pH of the composition is in the range of 2.0 to 7.0.

20. The pharmaceutical composition according to any one of claims 1-7, wherein the complex is in liquid form at 20-100 ℃.

21. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 19, comprising the steps of:

(a2) Mixing an aqueous matrix with the liquid obtained in step (a 1);

the preparation method further optionally comprises the following steps:

(a 2-1) mixing an aqueous matrix with a solvent to prepare a solution of the aqueous matrix, and mixing the aqueous matrix solution with the liquid obtained in the step (a 1);

and/or optionally comprising the steps of:

(a3) Stirring and mixing pharmaceutically acceptable permeation promoters and/or fragrances and solvents, mixing and stirring the mixture with the solution obtained in the step (a 2) or (a 2-1) to be homogeneous, and cooling the mixture to room temperature;

and/or optionally comprising the steps of:

22. An external preparation comprising the pharmaceutical composition according to any one of claims 1 to 19, characterized in that the preparation is administered topically.

23. The external preparation of a pharmaceutical composition according to claim 22, wherein the preparation is a cream, a patch, a gel, a film coating, a paint, a liniment, a plaster.