CN115737571B - Pentazocine Xin Zhiji and preparation method and application thereof - Google Patents

Abstract

The invention relates to a pentazocine pharmaceutical composition, which comprises pentazocine or pharmaceutically acceptable salt thereof, excipient, lactic acid, pH regulator and metal complexing agent, and the preparation process of the composition preparation is simple, the storage stability of the product is high, the compatibility of auxiliary materials is good, and the impurity content is low.

Description

Pentazocine Xin Zhiji and preparation method and application thereof

Technical Field

The invention relates to the field of medicinal preparations, in particular to a pentazocine preparation composition, a preparation method and application thereof.

Background

Pentazocine was successfully developed and marketed by the Windsor Wenslo group in 1967, a derivative of benzomorphinan, which has mixed agonism and antagonism on opioid receptors, mainly agonism on opioid kappa receptors, agonism on sigma receptors at a large dose, and partial agonism or weaker antagonism on mu receptors. Pentazocine is suitable for pain relief from moderate to severe pain, has wide clinical application, and is suitable for various pains. Such as cancer pain, traumatic pain, postoperative pain, and can also be administered preoperatively or preanesthetically as an adjunct to surgical anesthesia.

The lactate salt of pentazocine has been used in the development of parenteral formulations selected from subcutaneous injection, intravenous injection, intramuscular injection, epidural injection, intrasternal injection, infusion, etc., and since the water injection formulation has a certain limitation in stability and transportation and storage conditions, impurities are easily introduced, it is required to develop a lyophilized formulation which is stable in storage for a long period of time, high in safety, and small in irritation.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides a pharmaceutical composition, which comprises pentazocine or pharmaceutically acceptable salt thereof, excipient, lactic acid, pH regulator and metal complexing agent.

The pharmaceutically acceptable salt is selected from pentazocine hydrochloride, pentazocine Xin Rusuan salt (i.e. pentazocine lactate).

According to an embodiment of the invention, the excipient is selected from one or more of glucose, sodium chloride, mannitol, glycine, lactose, trehalose, maltose, sorbitol and dextran. Preferably, the excipient is selected from one or two of mannitol and sodium chloride.

According to an embodiment of the invention, the pharmaceutical composition further comprises an antioxidant. The antioxidant is selected from one or more of ascorbic acid and sodium salt thereof, isoascorbic acid and sodium salt thereof, cysteine, sodium metabisulfite, sodium sulfite, sodium bisulphite, sodium thiosulfate, vitamin C, di Ding Jia phenol and tocopherol. Preferably, the antioxidant is selected from vitamin C.

The metal complexing agent is selected from edetate, preferably EDTA-2Na.

The pH regulator is one or more selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, lactic acid, citric acid, boric acid, tartaric acid, sodium bicarbonate, phosphate buffer, citrate buffer and acetate buffer.

According to an embodiment of the invention, the pH of the pharmaceutical composition is in the range of 3.5-6.5, preferably 3.5-5.5, more preferably 4.5-5.0, e.g. 4.0,4.1,4.2,4.3,4.4,4.5,4.6,4.7,4.8,4.9,5.0,5.1,5.2,5.3,5.4,5.5.

According to an embodiment of the present invention, the pharmaceutical composition comprises, by weight, 10 to 20 parts of pentazocine or a pharmaceutically acceptable salt thereof, 40 to 100 parts of an excipient, 2 to 10 parts of lactic acid, 0.01 to 0.25 part of a metal complexing agent, and further, may further comprise 0.05 to 0.3 part of an antioxidant.

According to an embodiment of the invention, the pharmaceutical composition comprises, by weight, 10-15 parts of pentazocine or a pharmaceutically acceptable salt thereof, 60-80 parts of an excipient, 3-8 parts of lactic acid, 0.05-0.15 part of a metal complexing agent and 0.10-0.25 part of an antioxidant.

According to an embodiment of the invention, the excipient is a mixture of mannitol and sodium chloride, the weight ratio of mannitol to sodium chloride being 2-4:1, preferably 2.5-3.0:1.

According to an embodiment of the invention, the pharmaceutical composition comprises 11 parts of pentazocine lactate, 50 parts of mannitol, 18 parts of sodium chloride, 5 parts of lactic acid, 0.13 part of metal complexing agent and 0.20 part of antioxidant in parts by weight.

According to an embodiment of the invention, the pharmaceutical composition is a lyophilized formulation.

The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps:

1) Mixing proper amount of water, lactic acid with the prescription amount, antioxidant and metal complexing agent at 45-50 ℃; 2) Adding the prescribed amount of pentazocine or pharmaceutically acceptable salt thereof, and stirring to completely dissolve the pentazocine;

3) Adding excipient with the prescription amount, fully stirring and dissolving, adding a pH regulator, adding the rest water to 1000ml, adding active carbon for adsorption, and filtering to remove carbon;

4) Sterilizing, filtering, packaging, and lyophilizing to obtain the final product.

Advantageous effects

The pentazocine composition is suitable for freeze-dried preparations, and the preparation process is simple, the storage stability and the quality of the product are high, the compatibility of auxiliary materials is good, and the impurity content is low.

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. Unless otherwise indicated,% represents weight percent.

The structural formula of the pentazocine lactate is as follows (CAS No. 17146-95-1):

EXAMPLE 1 preparation of lyophilized preparation of the present invention

Prescription:

the preparation process comprises the following steps:

1) Mixing proper amount of water for injection, lactic acid with the prescription amount, antioxidant (vitamin C) and metal complexing agent (EDTA-2 Na) at 45-50 ℃;

2) Adding the prescribed amount of the pentazocine lactate, and stirring to completely dissolve the pentazocine lactate;

3) Adding excipient (mannitol, sodium chloride) with a prescription amount, fully stirring and dissolving, regulating the pH to about 4.5 by using a pH regulator (sodium hydroxide), adding the rest of injection water to 1000ml, adding active carbon, stirring, adsorbing for 20-25 minutes, and filtering to remove carbon;

4) Sterilizing and filtering the obtained liquid, filling the liquid into penicillin bottles, and sub-packaging 1ml of each bottle; freeze drying to remove water (the freeze drying temperature is controlled to be minus 45 ℃ to minus 30 ℃ for about 3 hours, and the vacuum drying is carried out at low temperature for about 12 to 15 hours), and pressing and plugging are carried out, thus obtaining the product.

EXAMPLE 2 formulation stability test

Referring to the preparation process of example 1, lyophilized formulations were prepared according to the following A-F formulations, and accelerated stability testing (temperature 40.+ -. 2 ℃ C., relative humidity 75%.+ -. 5% in dark conditions; HPLC determination) was performed on samples of the formulations. The results are shown in tables 1-2 below:

table 1: formulation prescription

Table 2: stability effect of the formulation

The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. 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 (4)

1. A pharmaceutical composition, which is characterized by comprising pentazocine Xin Ru acid salt, excipient, lactic acid, pH regulator and metal complexing agent; the excipient is selected from mannitol and sodium chloride; the metal complexing agent is selected from EDTA-2Na; the pH value of the pharmaceutical composition ranges from 3.5 to 5.5;

the pharmaceutical composition comprises, by weight, 10-20 parts of pentazocine Xin Ru acid salt, 40-100 parts of an excipient, 2-10 parts of lactic acid and 0.01-0.25 part of a metal complexing agent.

2. The pharmaceutical composition according to claim 1, further comprising an antioxidant selected from one or more of ascorbic acid or its sodium salt, isoascorbic acid or its sodium salt, cysteine, sodium metabisulfite, sodium sulfite, sodium bisulfite, sodium thiosulfate, vitamin C, di Ding Jia phenol, tocopherol.

3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition comprises 0.05-0.3 parts by weight of an antioxidant.

4. A method of preparing a pharmaceutical composition according to claim 2 or 3, comprising the steps of:

1) Mixing proper amount of water, the lactic acid with the prescription amount, the antioxidant and the metal complexing agent uniformly at the temperature of 45-50 ℃;

2) Adding the prescribed amount of pentazocine Xin Ru acid salt, and stirring to completely dissolve the pentazocine Xin Ru acid salt;

3) Adding excipient with the prescription amount, fully stirring and dissolving, adding a pH regulator, adding the rest water to 1000ml, adding active carbon for adsorption, and filtering to remove carbon;

4) Sterilizing, filtering, packaging, and lyophilizing to obtain the final product.