Amorphous substance of pamoic acid pentazocine and pharmaceutical composition thereof

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to an amorphous substance of pamoic acid pentazocine and a pharmaceutical composition of the amorphous substance. The amorphous substance of pentazocine pamoate has low solubility in water and other media, the stability and the slow release effect of pentazocine pamoate can be improved due to the low solubility of the amorphous substance, the action time can be effectively prolonged, and the amorphous substance can be used for preparing drugs for treating pain.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to an amorphous form of pentazocine tannate and a pharmaceutical composition thereof. Background Art

[0002] Postoperative pain is usually caused by tissue trauma (such as incision, traction, suture during surgery), and is an acute pain that occurs immediately after surgery (Treasure Island (FL): StatPearls Publishing, 2022). It persists during the process of tissue injury and repair in the body, seriously affecting the physical recovery and mental health of patients. The mechanism of postoperative pain (Research progress on the mechanism and treatment status of postoperative pain, 2020, 49: 1-5) is a complex process of multiple central and peripheral sensitizations. Surgical trauma directly damages the nerve endings at the site, leading to an inflammatory response, thereby releasing substances that cause pain such as serotonin and inflammatory factors; it can also cause an increase in the activity of spinal dorsal horn neurons, thus exacerbating the pain. The incidence of postoperative pain is high and usually lasts for several days. If not adequately controlled in the initial state, it may continue to develop into chronic pain. Therefore, long-acting analgesia meets the clinical needs of postoperative pain treatment.

[0003] Long-acting injectable drugs have now been widely used in the field of disease treatment (Journal of Guangdong Pharmaceutical University, 2015; 31(5): 584, West China Journal of Pharmaceutical Sciences, 2016; 31(3): 324-326). In the 1990s, the FDA approved the first long-acting injectable drug for atypical antipsychotics, risperidone (RISP) polymeric microspheres. Subsequently, long-acting injectable formulations of drugs such as fluphenazine (FLP), haloperidol (HAL), olanzapine (OLZ), aripiprazole (APZ), paliperidone (PALI) have also been approved for marketing. Existing long-acting injectable technologies mainly include prodrugs, microspheres, microcapsules, injectable implants, gels, in-situ depot, poorly soluble salts and other technologies (Int J Pharm, 2016; 499(1-2): 358-367).

[0004] The salt formation technology is generally a technology used to improve the solubility of insoluble compounds (Adv Drug DelivRev, 2007; 59(7): 603-616). The sparingly soluble salt technology, on the contrary, is to convert water-soluble drugs into sparingly soluble salts to control the drug release and extend the drug action time (Chinese Journal of New Drugs, 2013; 22(05): 547-555). As a simple approach in sustained-release preparations, the sparingly soluble salt technology has opened up a broader research space for the development of sustained-release preparations. Currently, the long-acting injectables using the sparingly soluble salt technology that have been marketed, such as olanzapine pamoate monohydrate injection, have reduced the dosing frequency from once a day to once every 2 weeks or once every 4 weeks, and the plasma half-life has been extended from 30 h to nearly 30 days (Int J Clin Pract, 2009; 63(1): 140-150). Although olanzapine pamoate injection shows good performance in bioavailability, biocompatibility and therapeutic effect, some adverse events still occur in some injection events. In intramuscular injection, the pH at the injection site is similar to the buffer salt solution with a pH of 7.4-7.6 in the laboratory, and there are still events of "Post-injection Delerium / Sedation Syndrome (PDSS)" in patients receiving olanzapine pamoate treatment. It is considered that the main reasons for these adverse events are the direct entry into the vein during injection or blood infiltration into the injection site due to blood vessel puncture, and the high solubility of drugs such as olanzapine pamoate in proteins and blood lipids.

[0005] Compared with other sustained-release technologies, this technology is only suitable for drugs that can form salts and there are few types of salts formed. Since such injectables do not have targeting properties and the residence time increases, while extending the drug half-life, it also increases the risk of adverse reactions. In addition, the release rate of the drug after salt formation is uncontrollable, lacking the flexibility of medication, and is not applicable to some drugs with high toxicity of themselves or degradation products.

[0006] Pentazocine, chemically named (2 R , 6 R , 11 R )-cis-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol, and its structural formula is as follows: ; Its hydrochloride and lactate are known to be clinically used for various pains, such as cancer pain, traumatic pain, postoperative pain, and can also be used for pre-operative or pre-anesthetic administration as an adjuvant for surgical anesthesia. The molecular formula of the base is: C 19 H27 NO, Molecular weight: 285.43. pKa1 = 8.0 (tertiary amine), pKa2 = 9.7 (phenolic hydroxyl group), melting point is 150 - 158 °C.

[0007] Long - acting salts of amine - containing pharmaceutical active ingredients, such as the pamoate and cinchomeronate families, have received relatively little attention and have limited commercial success. Currently, only one cinchomeronate, namely salmeterol cinchomeronate, is listed in the FDA's Orange Book of drugs and has been approved for the market. Similarly, currently only four pamoates have been approved for the market: hydroxyzine pamoate, imipramine pamoate, olanzapine pamoate, and triptorelin pamoate.

[0008] Pamoic acid, the structural formula is as follows: ; Molecular formula: C 23 H 16 O6, Molecular weight: 388.38, pKa1 = 2.51 (tertiary amine), pKa2 = 3.1 (phenolic hydroxyl group), melting point is about 280 °C (decomposition).

[0009] Prior - art patent documents: JPS5379870A and WO2010016219A1: disclose pentazocine and its acidic salts; CN113831251A and CN113845429A: a memantine pamoate crystal, its preparation method and application; CN113423686A: ketamine pamoate and its uses, K - vitamin pamoate and its uses; CN112752752A: a preparation method of escitalopram pamoate crystal form A; CN111233878A: a galantamine pamoate and its preparation method; CN111212640A: pamoates of monoamine anti - Parkinson drugs, their preparation methods and uses; CN106831594A: clonidine pamoate and its preparation method; CN109311832A: vortioxetine pamoate and its crystal form; WO2018177232A1: poorly soluble complexes or their solvates, pharmaceutical compositions and their applications.

[0010] Selection of active pharmaceutical ingredient (API) salts: Different salts of an API can have different properties. Such variations in the properties of different salts can provide a basis for improving formulations, for example, by promoting better processing or handling characteristics, improving dissolution profiles, or improving stability and shelf life. These variations in the properties of different salts can also provide improvements to the final dosage form, for example, if they act to improve bioavailability. Different salts of an API can also give rise to various polymorphs, which in turn can provide additional opportunities for providing improved drug substances and products.

[0011] Polymorphs, the occurrence of different crystal forms, are a property of some molecules and molecular complexes. A single compound such as pentazocine can give rise to various polymorphs with different crystal structures and physical properties such as melting point, thermal behavior (e.g., measured by thermogravimetric analysis - "TGA" or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD) patterns, infrared absorption fingerprints, Raman absorption fingerprints, and solid-state ( 13 C-) NMR spectra. One or more of these techniques can be used to distinguish between different polymorphic forms of a compound.

[0012] New salts and solid forms, as well as solvates, of a drug substance can provide advantageous properties such as ease of handling, ease of processing, storage stability, and ease of purification, or serve as a desirable intermediate crystal form to facilitate conversion to other salt or polymorphic forms. New polymorphic forms and solvates of pharmaceutically useful compounds can also provide opportunities to improve the performance characteristics (dissolution profiles, bioavailability, etc.) of drug products. For example, by providing products with different properties (e.g., different crystal habits, higher crystallinity, or polymorphic stability), it can provide better processing or handling characteristics, improved dissolution, or improved shelf life, expanding the repository of materials available to formulation scientists for formulation optimization. For at least these reasons, there is a need for additional pentazocine salts and solid forms.

[0013] It is well known that the pH of muscle tissue varies with exercise, stress, and injury, which can affect the solubility of drugs and thus the rate of absorption of injected drugs. Therefore, it is desirable to find an injectable sustained-release formulation in which the release rate of the active ingredient is minimally dependent on pH.

[0014] Currently, common general knowledge generally teaches that selecting a salt with the desired combination of properties remains a difficult semi-empirical choice that requires a trade-off selection of the properties of the salt form, but there is still a difficulty in evaluating which salt form is most suitable for screening a particular candidate drug.

[0015] The screening of drug salt forms is a difficult semi-empirical choice. The hygroscopicity of drugs can seriously affect the fluidity of drugs and even affect the stability of drugs. The solubility of drugs has a crucial impact on the preparation of pharmaceutical agents, drug dissolution, absorption, etc. However, it is difficult to increase the solubility of drugs without sacrificing the hygroscopicity of drugs and obtain candidate drug salts with appropriate drug stability, solubility, and hygroscopicity.

[0016] In addition, pentazocine is clinically applicable for analgesia in various surgical anesthetics, and can be used for anesthesia induction, intraoperative anesthesia, postoperative analgesia, etc.; it is applicable for postoperative analgesia in various surgical departments; it is applicable for analgesia in various endoscopic surgeries; it is applicable for analgesia in painless abortions; it has encouraging therapeutic effects in the analgesia and related behavioral symptoms of cancer patients. However, its potential has been limited by the short-acting and frequent side effects of medication, including salivation, nausea, dizziness, respiratory depression, physical dependence, etc. At the same time, its metabolic situation in the human body is complex and unpredictable, which has caused difficulties in the drug development of pentazocine.

[0017] Therefore, it is necessary to further search for new salts and polymorphs of pentazocine that have good therapeutic effects, few side effects, better pharmacokinetic properties, are suitable for drug formation, and have suitable and reliable formulation and preparation characteristics. Summary of the Invention

[0018] For the ordinary tablets of pentazocine (TALWIN), the drug dissolution is slow or cannot be completely dissolved after oral administration. At the same time, due to the influence of first-pass metabolism, the bioavailability is relatively low, only about 18% - 22%. At the same time, the metabolism is extensive, and large-scale post-marketing surveillance surveys show that the gastrointestinal side effects are extremely large. Although the bioavailability of the pentazocine injection (TALWIN) is high after intravenous injection, the elimination half-life in the body is short after intravenous injection, and the average residence time is short, which will lead to an increase in the number of drug administrations, resulting in a decrease in patient compliance and a low bioavailability, restricting its clinical application. Moreover, the rapid-release injection has a short drug effect time, mostly only lasting for 3 - 4 hours, and the postoperative pain relief time is short. Therefore, it is necessary to design and prepare a suitable pentazocine preparation to extend the duration of drug effect to meet the clinical needs.

[0019] The duration of action of pentazocine is short, forcing patients to take pentazocine frequently. In addition, like other opioid drugs, pentazocine is also considered to have the possibility of abuse. To solve this problem, pentazocine naloxone tablets have been marketed in the United States and Japan for oral administration, administered 3 times a day. Therefore, an alternative dosage form is needed, which can provide extended release of pentazocine, thereby reducing the dosing frequency. In addition, an alternative dosage form is needed to overcome the problems associated with oral administration and reduce the chance of abuse so that patients or other external sources cannot manipulate the release of the analgesic.

[0020] The inventors of the present invention have developed a new dosage form for parenteral administration that provides extended release of pentazocine. Since the analgesic effect of pentazocine has a short duration (up to 6 hours), extending the action of the drug will significantly benefit patients by continuously maintaining a therapeutic level of pain relief. The extended release of pentazocine also overcomes the problem of insufficient pain relief during oral treatment due to fluctuations in the dosing frequency. The present invention is achieved by the following technical solutions: The object of the present invention is to make up for the deficiencies in the prior art and provide a pentazocine pamoate having the structure shown in formula (I): ;

[0021] The pentazocine pamoate provided by the present invention is an amorphous powder. Using Cu-Kα radiation, its X-ray powder diffraction pattern is as Figure 1 shown.

[0022] The present invention also provides a method for preparing pentazocine pamoate, and the preparation method is: pentazocine and pamoic acid are salted in an organic solvent to obtain it, and the reaction formula is as follows: ; wherein the organic solvent refers to one or more of methanol, ethanol, isopropanol, n-butanol, acetone, butanone, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, ether, isopropyl ether, petroleum ether, n-hexane, tetrahydrofuran, dioxane, methyltetrahydrofuran, DMSO. During the screening of solvents, many cases where salts cannot be formed are described in the following comparative examples.

[0023] Another object of the present invention is to provide an injectable composition containing pentazocine pamoate, wherein the composition provides extended release of pentazocine for at least 48 hours. An injectable composition provided by an embodiment of the present invention includes pentazocine pamoate, wherein the composition provides extended release of pentazocine for up to one month, preferably up to 15 days, more preferably up to 7 days, and most preferably up to 5 days.

[0024] The injectable composition of the present invention can be formulated into a liquid composition of pentazocine pamoate for parenteral administration, which provides extended release. Pentazocine pamoate can be suspended and / or dispersed in an aqueous carrier or a non-aqueous carrier. The composition also includes one or more pharmaceutically acceptable excipients.

[0025] The injectable composition of pentazocine tannate according to the present invention forms a homogeneous solution or a water / non - aqueous suspension / dispersion when formulated as a liquid composition. Preferably, pentazocine tannate forms an aqueous suspension. Optionally, the liquid composition according to the present invention is lyophilized and can be re - formulated for injection before administration.

[0026] Preferably, the liquid preparation comprises pentazocine tannate. The particle size (D90) of the liquid composition or lyophilized powder of pentazocine tannate according to the present invention is less than 50 microns, preferably less than 30 microns, more preferably the size of the engineered particles is less than 15 microns, and most preferably the size of the engineered particles is less than 10 microns. Surprisingly, when formulated according to the present invention, it is observed that the particle size of pentazocine tannate interferes with the release of the drug. Therefore, particle size optimization is crucial for the desired release of the drug. Preferably, the particle size (D90) of the suspended or dispersed particles of pentazocine tannate in the liquid composition is less than 50 microns, more preferably less than 15 microns. In addition, after reconstituting the lyophilized powder with the required carrier, the particle size (D90) of the suspended or dispersed particles of pentazocine tannate in the liquid composition is less than 50 microns, more preferably less than 15 microns.

[0027] The pH value of the liquid composition prepared according to the present invention ranges from 4 to 9, preferably from 5.5 to 8.5.

[0028] The injectable aqueous suspension of pentazocine tannate can be used as a ready - to - use suspension or lyophilized powder to improve the physical and chemical stability of the preparation.

[0029] The lyophilized powder can be prepared by methods known in the art. Alternatively, cryoprotectants such as cryoprotective agents can be used during the lyophilization process. A cryoprotectant is a reagent that protects the formulated composition from the harmful effects of freezing. For injectable suspensions, cryoprotectants prevent caking caused by the lyophilization process. The type and amount of cryoprotectant used for the composition diluent are crucial for determining the injectability and syringeability of the composition after reconstitution of the lyophilized preparation. In addition, the process and duration of lyophilization are crucial for providing the desired cake or liquid suspension powder. Examples of cryoprotectants that can be used include, but are not limited to, mannitol, lactose, sucrose, trehalose, sorbitol, glucose, etc. The preferred cryoprotectants are mannitol and lactose.

[0030] The injectable composition of the present invention comprises a suitable aqueous carrier, which is water for injection, and optionally includes one or more of a suspending agent or viscosity modifier, a wetting agent, and optionally a preservative, a pH modifier, a buffer, an isotonicity - maintaining agent or an osmotic - maintaining agent, and a release - rate retardant.

[0031] In some embodiments of the present invention, the non-aqueous carriers comprised in the composition include, but are not limited to, cottonseed oil, dibutyl phthalate, diethyl phthalate, dimethyl ether, dimethyl phthalate, dimethyl sulfoxide, ethyl acetate, ethyl lactate, ethyl oleate, glycerol, furfuryl alcohol, isopropyl myristate, isopropyl palmitate, light mineral oil, medium-chain triglycerides (MCT), methyl lactate, mineral oil, monoethanolamine, octyldodecanol, olive oil, peanut oil, polyethylene glycol, castor oil, propylene carbonate, propylene glycol, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, triacetin, tributyrin, triethanolamine, triethyl citrate, triolein, alcohol, almond oil, benzyl alcohol, benzyl benzoate, butylene glycol, carbon dioxide or mixtures thereof. Alternatively, pharmaceutically acceptable excipients, such as thickeners, preservatives, antioxidants and any combination thereof, may be added to the non-aqueous carrier.

[0032] In some embodiments of the present invention, thickeners are used, including but not limited to aluminum monostearate, ethyl cellulose, triglycerides, hydrogenated castor oil, etc. or mixtures thereof.

[0033] The injection composition according to the present invention further comprises one or more pharmaceutically acceptable ingredients selected from, but not limited to, buffers, wetting agents, viscosity modifiers, sustained release rate agents, isotonic agents, preservatives, stabilizers, pH regulators, plasticizers, etc. or mixtures thereof.

[0034] In some embodiments of the present invention, wetting agents are used, including but not limited to lecithin, polyoxyethylene and polyoxypropylene ethers, sodium deoxycholate, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, sodium docusate, glycine, phospholipids, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene monolauryl ether, alkyl phenyl polyoxyethylene ethers, polyoxyethylene-polyoxypropylene copolymer (poloxamer), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (such as polysorbate 80 (Tween 80) and polysorbate 20 (Tween 20)), polyoxyethylene stearate, sodium lauryl sulfate, sorbitan esters, trioctanoin, etc. or mixtures thereof.

[0035] In some embodiments of the present invention, sustained release rate agents are used, including but not limited to modified dextran, sucrose acetate isobutyrate, medium-chain triglycerides, glucose, polymer solutions (prepared by mixing polymers in suitable solvents), etc. or mixtures thereof.

[0036] The stabilizers used in some embodiments of the present invention include, but are not limited to, mannitol, sorbitol, sucrose, glycine, lactose, amino acids, saccharides, α-tocopherol, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, fumaric acid, malic acid, monothioglycerol, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, sodium sulfite, tartaric acid, vitamin E, etc. or mixtures thereof.

[0037] In some embodiments of the present invention, pH regulators are used, including but not limited to sodium hydroxide, hydrochloric acid, etc. or mixtures thereof.

[0038] In some embodiments of the present invention, plasticizers are used, including but not limited to polyethylene glycol, stearic acid, palmitic acid, cholesterol, cetyl palmitate, poloxamer, etc. or mixtures thereof.

[0039] The preservatives used in the present invention are selected in an amount to maintain the composition. Suitable preservatives used in some embodiments of the present invention include but are not limited to benzalkonium chloride, methyl, ethyl, propyl or butyl p-hydroxybenzoate, benzyl alcohol, phenethyl alcohol, phenylethyl alcohol, benzethonium chloride, chlorobutanol, potassium sorbate, or combinations thereof.

[0040] In some embodiments of the present invention, buffering agents are used, including but not limited to citrates, acetates or phosphates or mixtures thereof.

[0041] In some embodiments of the present invention, isotonic agents are used, including but not limited to sodium chloride, potassium chloride, sugars and sugar alcohols including but not limited to glucose, sucrose, trehalose or glycerol, and any component from the group of amino acids, sugars, salts, alone or in combination.

[0042] The viscosity regulators used according to the present invention are known to those skilled in the art of the prior art, including but not limited to gum arabic, agar, alginic acid, bentonite, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, carrageenan, colloidal silica, ethyl cellulose, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hydroxypropyl starch, hydroxypropyl cellulose, methyl cellulose, myristyl polyethylene glycol, polyvinyl phthalate, polyvinyl alcohol, potassium chloride, povidone starch, stearyl alcohol, sucrose, or mixtures thereof.

[0043] The lipids used according to the present invention are of synthetic or semi-synthetic origin. Examples of lipids known to those skilled in the art include, but are not limited to, phosphatidylcholine, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, phosphatidylglycerol, cholesterol, etc. or mixtures thereof. In some embodiments of the present invention, the solid lipids comprised in the composition include tristearate, trilaurin, tripalmitate, glycerol behenate, lauric acid, cholesterol, stearic acid, palmitic acid, etc. or mixtures thereof.

[0044] In some embodiments of the present invention, non-ionic surfactants are used, including but not limited to acetyl alcohol, coconut amide diethanolamine, coconut amide monoethanolamine, poloxamer, polyglycerol, polysorbate, [unclear term], Tween and mixtures thereof.

[0045] However, the present invention will be further illustrated by the following examples, but its scope is not limited to these examples. Description of the Drawings

[0046] Figure 1 X-ray diffraction pattern of pentazocine tannate.

[0047] Figure 2 Structural formula of pentazocine tannate.

[0048] Figure 3 Hydrogen spectrum of pentazocine tannate.

[0049] Figure 4 Carbon spectrum of pentazocine tannate.

[0050] Figure 5 TGA of pentazocine tannate.

[0051] Figure 6 DSC of pentazocine tannate.

[0052] Figure 7 IR of pentazocine tannate.

[0053] Figure 8 XRD of pentazocine tannate crystals.

[0054] Figure 9 Comparison of pK curves between pentazocine tannate aqueous suspension and pentazocine base suspension in rats.

[0055] Figure 10 Comparison of pK curves of pentazocine tannate lyophilized powder in beagle dogs. Detailed Description of the Invention

[0056] The following examples can further describe the present invention. However, these examples should not be construed as limiting the scope of the present invention. Example 1: Preparation of Pentazocine Tannate

[0057] 0.68 g of tannic acid and 20 ml of tetrahydrofuran were added to a 50 ml reaction flask, heated to 55 - 60 °C, and 1.0 g of pentazocine was slowly added. After dissolution, the mixture was stirred at a constant temperature for 30 min. After stirring, it was concentrated to dryness, 10 ml of methanol was added, heated to reflux until dissolved, and slowly cooled to 0 - 5 °C. A viscous oily substance was precipitated, which gradually hardened into a blocky amorphous substance. Example 2: Preparation of Pentazocine Tannate

[0058] 0.68 g of tannic acid and 20 ml of tetrahydrofuran were added to a 50 ml reaction flask, heated to 55 - 60 °C, and 1.0 g of pentazocine was slowly added. After dissolution, the mixture was stirred at a constant temperature for 30 min. After stirring, it was concentrated to dryness, 40 ml of isopropanol was added, heated to reflux until dissolved, and slowly cooled to 20 - 25 °C. Granular solids were precipitated, stirred overnight, filtered, and the filter cake was dried in vacuo to obtain 1.12 g of yellow amorphous solid, with a yield of 66.66%. Example 3: Preparation of Pentazocine Tannate

[0059] 0.68 g of tannic acid and 40 ml of isopropanol were added to a 50 ml reaction flask, heated to reflux, and 1.0 g of pentazocine was slowly added. After dissolution, the mixture was stirred at a constant temperature for 30 min. After stirring, it was slowly cooled to 20 - 25 °C. Granular solids were precipitated, stirred overnight, filtered, and the filter cake was dried in vacuo to obtain 1.21 g of yellow amorphous solid, with a yield of 72.02%. Example 4: Preparation of Pentazocine Tannate

[0060] 6.8 g of tannic acid and 400 ml of isopropanol were added to a 500 ml reaction flask, heated to reflux, and 10 g of pentazocine was slowly added. After dissolution, the mixture was stirred at a constant temperature for 30 min. After stirring, it was slowly cooled to 20 - 25 °C. Granular solids were precipitated, stirred overnight, filtered, and the filter cake was dried in vacuo to obtain 13.1 g of yellow amorphous solid, with a yield of 77.97%. Example 5: Preparation of Pentazocine Tannate

[0061] 68 g of tannic acid and 4000 ml of isopropanol were added to a 5000 ml reaction flask, heated to reflux, and 100 g of pentazocine was slowly added. After dissolution, the mixture was stirred at a constant temperature for 30 min. After stirring, it was slowly cooled to 20 - 25 °C. Granular solids were precipitated, stirred overnight, filtered, and the filter cake was dried in vacuo to obtain 119 g of yellow amorphous solid, with a yield of 70.83%. Example 6: Preparation of Pentazocine Tannate

[0062] 0.68 g of pamoic acid and 40 ml of isopropanol were added to a 50 ml reaction flask, heated to reflux, and 1.0 g of pentazocine was slowly added. After dissolution was clear, the mixture was stirred at a constant temperature for 30 min. After stirring was completed, the temperature was slowly decreased to 0 - 5 °C, granular solids precipitated, and the mixture was stirred overnight, filtered, and the filter cake was dried under vacuum to obtain 1.39 g of a yellow amorphous solid with a yield of 82.64%. Example 7: Preparation of Pentazocine Pamoate

[0063] 0.68 g of pamoic acid and 50 ml of isopropanol were added to a 50 ml reaction flask, heated to reflux, and 1.0 g of pentazocine was slowly added. After dissolution was clear, the mixture was stirred at a constant temperature for 30 min. After stirring was completed, the temperature was slowly decreased to 0 - 5 °C, granular solids precipitated, and the mixture was stirred overnight, filtered, and the filter cake was dried under vacuum to obtain 1.19 g of a yellow amorphous solid with a yield of 70.83%. Example 8: Preparation of Pentazocine Pamoate

[0064] 0.68 g of pamoic acid and 60 ml of isopropanol were added to a 50 ml reaction flask, heated to reflux, and 1.0 g of pentazocine was slowly added. After dissolution was clear, the mixture was stirred at a constant temperature for 30 min. After stirring was completed, the temperature was slowly decreased to 0 - 5 °C, granular solids precipitated, and the mixture was stirred overnight, filtered, and the filter cake was dried under vacuum to obtain 1.23 g of a yellow amorphous solid with a yield of 73.21%. Example 9: Preparation of Pentazocine Pamoate

[0065] 1.36 g of pamoic acid and 20 ml of tetrahydrofuran were added to a 50 ml reaction flask, heated to 55 - 60 °C, and 1.0 g of pentazocine was slowly added. The mixture was stirred at a constant temperature for 30 min, and insoluble substances were removed by filtration. The filtrate was concentrated to dryness, 40 ml of isopropanol was added, heated to reflux until dissolution was clear, then slowly cooled to 20 - 25 °C, granular solids precipitated, and the mixture was stirred overnight, filtered, and the filter cake was dried under vacuum to obtain 1.02 g of a yellow amorphous solid with a yield of 60.71%. Example 10: Preparation of Pentazocine Pamoate

[0066] 1.36 g of pamoic acid, 1.0 g of pentazocine, and 20 ml of tetrahydrofuran were added to a 50 ml reaction flask, heated to 65 - 70 °C, and stirred at a constant temperature for 30 min. Insoluble substances were removed by filtration. The filtrate was concentrated to dryness, 40 ml of isopropanol was added, heated to reflux until dissolution was clear, then slowly cooled to 20 - 25 °C, granular solids precipitated, and the mixture was stirred overnight, filtered, and the filter cake was dried under vacuum to obtain 1.12 g of a yellow amorphous solid with a yield of 66.66%. Example 11: Preparation of Pentazocine Pamoate

[0067] 1.36 g of pamoic acid and 40 ml of isopropanol were added to a 50 ml reaction flask. The mixture was heated to 55 - 60 °C, and 1.0 g of pentazocine was slowly added. The mixture was kept warm and stirred for 30 min, and the insoluble substances were removed by filtration. The filtrate was slowly cooled to 20 - 25 °C to precipitate granular solids. The mixture was stirred overnight, filtered, and the filter cake was dried in vacuo to obtain 1.19 g of a yellow amorphous solid with a yield of 70.83%. Example 12: Spectral Analysis

[0068] Appendix Figure 3 1H-NMR spectrum of pentazocine pamoate 1 1H-NMR (400 MHz, DMSO / TMS, ppm): Δδ 10.84 (1H, s, -COOH); δ 9.45 (1H, s, -COOH); δ 8.31 - 8.25 (4H, m, benzene ring of pamoic acid); δ 7.74 - 7.72 (2H, d, benzene ring of pamoic acid); δ 7.21 - 7.17 (2H, t, benzene ring of pamoic acid); δ 7.10 - 7.02 (4H, m, benzene ring of pamoic acid and pentazocine); δ 6.77 - 6.69 (4H, m, benzene ring of pamoic acid and pentazocine); δ 5.42 - 5.39 (2H, t, -CH=C-); δ 4.77 (2H, s, Ph-CH2-Ph); δ 3.86 - 3.73 (8H, m, phenolic hydroxyl, -CH2-); δ 3.21 - 2.98 (3H, m, -CH2-, -CH-); δ 2.28 - 2.27 (2H, d, -CH-); δ 2.08 - 2.02 (2H, t, -CH2-); δ 1.79 - 1.76 (12H, d, -CH3); δ 1.56 - 1.36 (8H, m, -CH2-); δ 1.08 - 1.07 (7H, m, -CH 3、 -CH-); δ 0.87 - 0.85 (6H, d, -CH3); Appendix Figure 4 13C-NMR spectrum of pentazocine pamoate 1 13C-NMR (400 MHz, DMSO / TMS, ppm): 172.81,156.90,156.43,142.42,140.73,135.93,129.92,129.71,129.12,126.92,126.81,124.22,123.65,122.09,121.63,120.10,114.61,114.43,112.53,62.57,58.14,51.65,45.66,35.45,34.77,29.43,26.32,26.01,24.83,22.65,20.44,18.67,13.50; Appendix Figure 6 DSC of pentazocine tannate. The glass transition of this product occurs at 55.27°C to 169.01°C; Appendix Figure 5 TGA of pentazocine tannate. This product begins to melt and decompose at about 141.39°C; Appendix Figure 1 XRD of pentazocine tannate. This product is amorphous; (Test conditions: XRD: performed on a Shimadzu 6100 diffractometer using Cu-Kα X-rays with a wavelength of 1.54 nm, 40 kV, and 30 mA. Before testing, the performance of the instrument was checked using corundum. The test sample was placed on a non-reflective plate at room temperature. Test conditions: scanning range 5 - 90°, 10° / min); Appendix Figure 7 IR of pentazocine tannate: ; Comparative Example 1: Preparation of crystalline pentazocine tannate Dissolve 500 mg of amorphous pentazocine tannate from Example 2 in a mixture of 3 mL of acetone and 0.5 mL of water, and dissolve at 60°C. Slowly cool the solution to room temperature and stir for 3 hours to obtain pentazocine tannate solid, which is collected, washed, and dried. Characterize the solid by XRPD, and the XRPD pattern is as shown in the appendix Figure 8 as follows: ; From the appendix Figure 8 it can be seen that pentazocine tannate prepared by the method of Comparative Example 1 has obvious absorption peaks at 11.083, 11.563, 12.475, 16.912, 17.236, etc., indicating that the product obtained by this method is in crystal form.

[0069] Comparative Example 2: Preparation of pentazocine tannate 0.68g of pamoic acid and 20ml of tetrahydrofuran were added to a 50ml reaction bottle, heated to 55-60℃, and 1.0g of pentazocine was slowly added to dissolve, and the mixture was stirred for 30min. After stirring, the mixture was concentrated to dryness, and 10ml of propanol was added. The mixture was heated to reflux and dissolved, and the temperature was slowly lowered to 0-5℃ for crystallization for 6h. No solid was precipitated, and the mixture was placed in a refrigerator and frozen overnight (-20℃), and a layer of oil was precipitated.

[0070] Comparative Example 3: Preparation of Pentazocine Pamoate 0.68g pamoic acid and 20ml tetrahydrofuran were added to a 50ml reaction bottle, heated to 55-60℃, 1.0g pentazocine was slowly added, dissolved, and stirred for 30min. After stirring, the mixture was concentrated to dryness, 30ml n-butanol was added, the mixture was heated to 70-80℃, dissolved, and slowly cooled to 20-25℃. A viscous oily substance was precipitated, and stirred overnight without any change.

[0071] Comparative Example 4: Preparation of Pentazocine Pamoate 0.68g pamoic acid and 20ml tetrahydrofuran were added to a 50ml reaction bottle, heated to 55-60℃, 1.0g pentazocine was slowly added, dissolved, and stirred for 30min. After stirring, the mixture was concentrated to dryness, 30ml acetonitrile was added, the temperature was raised to reflux, and the undissolved oil was removed by filtration. The filtrate was slowly cooled to 20-25℃, and a viscous oil was precipitated. The mixture was stirred overnight, and the oil at the bottom became a blocky solid and adhered to the wall.

[0072] Comparative Example 5: Preparation of Pentazocine Pamoate 0.68g of pamoic acid and 20ml of N,N-dimethylformamide were added to a 50ml reaction bottle, heated to 55-60°C, 1.0g of pentazocine was slowly added, dissolved, and stirred for 30 minutes. The temperature was slowly lowered to 0-5°C, stirred overnight, and no solid was precipitated.

[0073] Comparative Example 6: Preparation of Pentazocine Pamoate 0.68g pamoic acid and 20ml dioxane were added to a 50ml reaction bottle, heated to 55-60℃, 1.0g pentazocine was slowly added, dissolved, stirred for 30min, slowly cooled to 0-5℃, stirred overnight, and a viscous oily substance was precipitated.

[0074] Comparative Example 7: Preparation of Pentazocine Pamoate 0.68g of pamoic acid and 20ml of N-methylpyrrolidone were added to a 50ml reaction bottle, heated to 55-60°C, and 1.0g of pentazocine was slowly added to dissolve, and stirred for 30 minutes. The temperature was slowly lowered to 0-5°C, and stirred overnight, and no solid was precipitated.

[0075] Comparative Example 8: Preparation of Pentazocine Pamoate Add 0.68 g of pamoic acid and 20 ml of methyltetrahydrofuran into a 50 ml reaction flask, heat to 55 - 60 °C, slowly add 1.0 g of pentazocine, dissolve until clear, keep warm and stir for 30 min. Slowly cool down to 0 - 5 °C, stir overnight, and a viscous oily substance will precipitate.

[0076] Comparative Example 9: Preparation of pentazocine pamoate Add 0.68 g of pamoic acid and 20 ml of N,N-dimethylformamide into a 50 ml reaction flask, heat to 55 - 60 °C, slowly add 1.0 g of pentazocine, dissolve until clear, keep warm and stir for 30 min. Slowly add 20 ml of isopropyl ether, cool down to 20 - 25 °C, and an oily substance will precipitate.

[0077] Comparative Example 10: Preparation of pentazocine pamoate Add 0.68 g of pamoic acid and 20 ml of dimethyl sulfoxide into a 50 ml reaction flask, heat to 55 - 60 °C, slowly add 1.0 g of pentazocine, dissolve until clear, keep warm and stir for 30 min. Slowly cool down to 0 - 5 °C, stir overnight, and no solid will precipitate.

[0078] Solubility test: In this invention, the solubility (at 25 °C) of pentazocine base, pentazocine pamoate crystals (Comparative Example 1), and amorphous pentazocine pamoate in water was investigated. The specific experimental steps were as follows: Dissolve pentazocine base, pentazocine pamoate crystals, or amorphous pentazocine pamoate in water, 0.01 mol / L HCl solution, and pH 6.8 PBS to prepare corresponding saturated solutions. Shake the saturated solutions in a 25 °C constant temperature water bath for 24 h. After filtering the liquid medicine, determine the content by HPLC and calculate the corresponding solubility. The results are as follows: ; The results showed that: Compared with pentazocine base and pentazocine pamoate crystals, the solubility of the amorphous pentazocine pamoate prepared in this invention in water and other media was significantly reduced, showing good low solubility characteristics. Its lower solubility can improve the stability and sustained-release effect of pentazocine pamoate.

[0079] Preparation of pentazocine base solutions in Comparative Examples 11, 12, and 13 ; Preparation method: (1) Take the prescribed amount of pentazocine base and add it to 90% oil in portions while stirring. After mixing evenly, add oil to the full volume; (2) Put the evenly mixed primary suspension into a ball mill and grind it. The rotation speed is 800 rpm. Grind for 3 min in each cycle, stop for 5 min, and grind for a total of 5 cycles.

[0080] Comparative Example 14: Preparation of Pentazocine Hydroxy-Naphthoate Suspension Injection ; Preparation method: Add the prescribed amount of pentazocine salt to the aqueous carrier, continuously stir to form a uniform paste, and then supplement the remaining carrier to the fixed volume. Put it into a ball mill for grinding, with a rotation speed of 800 rpm, grind for 3 minutes in each cycle, stop for 5 minutes, and grind for a total of 5 cycles. Adjust the pH value of the solution to 7.0 - 7.5 by adding lactic acid.

[0081] Examples 13, 14, 15, 16: Preparation of Pentazocine Hydroxy-Naphthoate (Amorphous) Aqueous Suspension ; Preparation method: Weigh the excipient components precisely, add them to water, stir until dissolved, and adjust the pH to 7.4 with 1M NaOH aqueous solution. Weigh pentazocine hydroxy-naphthoate precisely and add it to the dispersion medium in small portions at a rate of 200 rpm. After complete addition, continue stirring for 1 h, and then carry out grinding using a media mill: the grinding media are zirconia beads with a diameter of 0.8 μm, the rotation speed is 2500 rpm, the pump speed is at gear 4, the air pressure is 4.0 - 4.5 bar, and the grinding time is 2 minutes. After grinding, aliquot it into vials, and take 1.0 mL of the ground suspension in each vial to obtain the product.

[0082] Examples 17, 18: Preparation of Freeze-Dried Product of Pentazocine Hydroxy-Naphthoate Aqueous Suspension ; Preparation method: Add pentazocine hydroxy-naphthoate to the excipients, homogenize it using a high-speed homogenizer (15000 revolutions per minute for 15 minutes) to achieve uniform dispersion, and carry out particle size reduction treatment using a high-pressure homogenizer (5000 PSI for 15 minutes, then 10000 PSI for 15 minutes, and then 15000 PSI for 10 minutes). Take 3.2 mL of the suspension and lyophilize it in a 5 mL vial, and reconstitute it with water of the initial volume. It was observed that the formulation containing lactose as a cryoprotectant was more easily reconstituted than the formulation containing mannitol as a cryoprotectant.

[0083] Lyophilization cycle: ; Example 19: Preparation of Freeze-Dried Product of Pentazocine Hydroxy-Naphthoate Aqueous Suspension ; Preparation method: Add pentazocine tannate to the excipients, and homogenize it using a high-speed homogenizer (15,000 rpm for 15 minutes) to achieve uniform dispersion. Then, subject the dispersion to particle size reduction treatment using a high-pressure homogenizer (5000 PSI for 15 minutes, then 10000 PSI for 15 minutes, and then 15000 PSI for 10 minutes). Take 3 mL of the suspension and dispense it into 5 mL vials, and perform freeze-drying. After freeze-drying, reconstitute it with water of the initial volume. The obtained freeze-dried cake has a complete structure and can be reconstituted with water of the initial volume.

[0084] Freeze-drying cycle: ; Examples 20 and 21: Preparation of freeze-dried products of aqueous suspension of pentazocine tannate ; Preparation method: Add povidone K12 to water for injection and stir until completely dissolved. Subsequently, add Tween 80 and lactose successively under continuous stirring and stir until completely dissolved to form a uniform solution. Add pentazocine tannate to the above solution, stir to disperse it, and then homogenize it to achieve the desired particle size distribution. Dispense the final suspension into 5 mL glass vials and perform freeze-drying according to the freeze-drying process parameters of Example 19. After freeze-drying is completed, reconstitute the obtained freeze-dried cake with a mixed solution of sodium dihydrogen phosphate dihydrate and water.

[0085] Example 22: Pharmacokinetic study in rats 1 High-performance liquid chromatography analysis method in vivo Chromatographic conditions: Use octadecylsilane-bonded silica gel as the filler (specification 4.6×100 mm; 2.6 μm); use 15 mmol / L sodium borate (adjusted to pH 10.0 with 10 mol / L sodium hydroxide) as mobile phase A and methanol as mobile phase B for gradient elution; the flow rate is 0.5 mL per minute; the column temperature is 40 °C; the detection wavelength is 225 nm; the injection volume is 20 μL.

[0086] 2 Preparation of plasma samples Blank plasma sample: Take blank plasma from rats, after thawing, accurately measure 100 μL and transfer it to a 1.0 mL centrifuge tube, add 600 μL of 4% glacial acetic acid methanol, vortex mix for 5 min, centrifuge at 9000 rpm for 10 min to precipitate proteins, aspirate the supernatant to a 1.0 mL centrifuge tube, and dry it at 40 °C. Dissolve the residue in methanol, vortex oscillate for 6 min, sonicate for 15 min, centrifuge at 13000 rpm for 20 min, and the supernatant is the blank plasma sample solution.

[0087] Plasma samples after administration: Take the plasma of rats after administration. After thawing, accurately measure 100 μL and transfer it into a 1.0 mL centrifuge tube. Add 10 μL of internal standard metazocine (1 μg / mL, dissolved in methanol), and vortex for 1 min to mix evenly. Add 600 μL of 4% glacial acetic acid in methanol, vortex for 5 min, centrifuge at 9000 rpm for 1 min to precipitate proteins, aspirate the supernatant into a 1.0 mL centrifuge tube, and evaporate to dryness at 40 °C. Redissolve the residue in methanol, vortex for 6 min, and sonicate for 15 min to fully dissolve the drug. Then centrifuge at 13000 rpm for 20 min, and the supernatant is the plasma sample solution after administration.

[0088] 3 Administration regimen and sample collection Randomly divide 30 rats into five groups, with 6 rats in each group. Intramuscularly inject the products of Comparative Example 14, Example 13, 14, 15, and 16 of the present invention at a dosage of 125 mg / kg. Collect blood from the orbital vein of rats at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48 h, 96 h, 144 h, 192 h, and 240 h after administration. Each time, collect about 0.25 mL of blood and add it to an anticoagulant tube treated with sodium heparin. Centrifuge at 4000 rpm for 10 min to separate the upper plasma, and store it at -20 °C for analysis and detection.

[0089] 4 Detection and data processing of plasma samples Take the plasma samples after administration and process them according to the method under 2 Preparation of plasma samples. Inject the samples under the chromatographic conditions in 1 High-performance liquid chromatography analysis method in vivo. Substitute the ratio of the peak areas of the main drug and the internal standard peak into the standard curve to calculate the blood drug concentration, and use Phoenix software to process the results and calculate the relevant pharmacokinetic parameters.

[0090] 5 Results: See the appendix Figure 9 。

[0091] The results show that the compounds of the present invention can be slowly, continuously, and stably released and converted into pentazocine in vivo, thereby exerting a long-acting effect. At the same time, they are released smoothly to achieve the long-acting release effect.

[0092] Example 23: Pharmacokinetic study in Beagle dogs Other treatment methods are the same as in Example 22. Administer the preparations prepared according to Examples 20 and 21 to male Beagle dogs. Each group (N = 6) is intramuscularly injected with a single dose of the preparation (equivalent to 20 mg / kg of tapentadol base). Collect blood samples at predetermined time intervals to determine the content of pentazocine. The results are as shown in the appendix Figure 10 which shows that the smaller the particle size, the faster the release in vivo and the higher the concentration.

Claims

1. An amorphous form of pentazocine tannate, characterized in that, The pentazocine tannate has the structure shown in formula (I): 。 2. A composition comprising an amorphous form of the pentazocine tannate according to claim 1.

3. The composition according to claim 2, which is an injectable composition.

4. The composition according to claim 2 or 3, characterized in that, The composition provides extended release of pentazocine for at least 48 hours.

5. The composition according to claim 4, wherein The D90 of the particle size of the amorphous form of pentazocine tannate is less than 50 microns.

6. The composition according to claim 4, wherein The composition is made into an injection solution or a lyophilized powder for liquid form.

7. The composition according to claim 2, characterized in that, The release of pentazocine lasts up to one month.

8. The composition according to claim 2, characterized in that, The D90 of the particle size of the amorphous form of pentazocine tannate is less than 30 microns, and the composition provides extended release of pentazocine.

9. The composition according to claim 8, characterized in that, The D90 of the particle size of the amorphous form of pentazocine tannate is less than 15 microns, and the composition provides extended release of pentazocine.

10. The composition according to claim 9, characterized in that, The D90 of the particle size of the amorphous form of pentazocine tannate is less than 10 microns, and the composition provides extended release of pentazocine.

11. The composition according to claim 7, characterized in that, The release time of pentazocine lasts up to 7 days.

12. The composition according to claim 7, wherein, The release time of pentazocine lasts up to 5 days.

13. Use of the amorphous form of the pentazocine tannate according to claim 1 or the composition according to any one of claims 2-12 in the preparation of drugs for acute and chronic pain.

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