Preparation method and application of penehyclidine hydrochloride new dosage form

Abstract

The invention discloses a preparation method and clinical application of a penehyclidine hydrochloride oral liquid preparation. Wherein the weight volume ratio of penehyclidine hydrochloride to the auxiliary components is (1: 5000)-(1: 100000). The invention develops a novel medicine dosage form related to the penehyclidine hydrochloride as well as an administration route and clinical application which are expanded according to the developed novel dosage form. The penehyclidine hydrochloride which is successfully developed and sold in the market is an injection, is used for inhibiting gland secretion and treating organophosphorus poisoning by administration before anesthesia, and has limited clinical application indications. The novel medicine adopts oral systemic administration and is convenient to use, so that the clinical application of the novel medicine can be greatly widened, and new clinical indications of penehyclidine hydrochloride can be developed to the maximum extent to realize the medical value of the penehyclidine hydrochloride.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to the preparation method and application of a new dosage form of pentoxyverine hydrochloride. The preparation method of the new dosage form specifically refers to the formulation and preparation process of an oral solution dosage form. The new applications include biliary colic, gastric colic, renal colic, intestinal colic caused by smooth muscle spasm due to various reasons, dysmenorrhea, etc. It can also be used for gastroscopy, colonoscopy, laparoscopy and their surgeries, gallbladder surgery, myomectomy, curettage, etc. Background Technology

[0002] Pentylcholine hydrochloride is a novel selective anticholinergic drug independently developed in my country. It exhibits selective antagonistic effects on M1, M3, N1, and N2 receptors, demonstrating strong anticholinergic activity in both the central and peripheral nervous systems, while having no significant effect on M2 receptors. Currently, the clinically approved formulation of pentylcholine hydrochloride is an injectable form, approved for use as a pre-anesthetic medication to suppress glandular secretion and as an emergency treatment for organophosphorus pesticide poisoning. As an anticholinergic drug, pentylcholine hydrochloride has a wide range of pharmacological effects; therefore, it is necessary to explore new applications to maximize its clinical value.

[0003] Pentyl quinolone hydrochloride is rapidly absorbed after injection or oral administration and widely distributed in the blood, smooth muscle, glands, trachea, bronchi, and other sites, providing a basis for the development of new dosage forms and indications.

[0004] Existing research (Lin Xuan, Liang Ying. Clinical Exploration of Gastrointestinal Antispasmodics, Proceedings of the 2016 Guangdong Provincial Pharmacist Week Conference) aims to explore the efficacy of anticholinergic drugs—gastrointestinal antispasmodics—in relieving gastrointestinal smooth muscle spasms. Methods: Clinical drug analysis was conducted on 100 hospitalized patients with gastrointestinal diseases to identify relevant information about gastrointestinal antispasmodics. Results: Gastrointestinal antispasmodics are suitable for symptoms such as hyperacidity, stomach pain, gastric and duodenal ulcers, renal colic, bladder irritation, and gastritis. Conclusion: Atropine sulfate is the most effective drug for relieving gastrointestinal smooth muscle spasms, but it has significant side effects and the dosage is difficult to control; Belladonna extract (compound belladonna) mainly targets gastric and duodenal ulcers and mild gastrointestinal spasms, providing analgesia and inhibiting secretion; Propranolol (bromopropylate) has a selective effect on gastrointestinal smooth muscle, resulting in a sustained and strong inhibitory effect. In addition, other drugs such as scopolamine bromide (Antispasmodic), isocoridine hydrochloride, pinaverium bromide (Deshute), and belladonna tincture are also in use.

[0005] Existing technology (Jiang Zhongcheng. Which drugs should be chosen for stomach diseases, Renren Health 2012 (01) Research shows that in clinical practice, commonly used antispasmodic and analgesic drugs include atropine sulfate, belladonna, scopolamine hydrobromide (654-2), propantheline, and gastric ulcer. Because they have the effects of inhibiting gastric acid secretion and relaxing gastrointestinal smooth muscle, they are often used in clinical practice to treat many acute diseases of the digestive tract. However, the elderly must be cautious when taking these drugs. In addition to their antispasmodic and analgesic effects, they also have the effects of dilating pupils and increasing intraocular pressure. After taking them, they are very likely to induce or aggravate the symptoms of glaucoma. In addition, the elderly with benign prostatic hyperplasia, hyperthyroidism, chronic bronchitis, hypotonia, and hemorrhagic proctitis should not use them. When taking the drugs, symptoms such as palpitations, shortness of breath, and chest tightness may also occur. Cardiovascular patients should also use them with caution.

[0006] Existing research (Yang Wenjun, Jian Huasheng. Clinical observation of 96 cases of acute biliary colic treated with pentoxyverine hydrochloride, Proceedings of the 11th National Conference on Emergency Medicine and the 20th Anniversary Celebration of the Founding of the Emergency Medicine Branch of the Chinese Medical Association) has shown that pentoxyverine hydrochloride is effective in treating biliary colic. Methods: Patients with biliary colic were randomly divided into a treatment group (pentoxyverine hydrochloride group) and a control group (atropine sulfate group). The antispasmodic and analgesic effects, as well as changes in heart rate and blood pressure, were observed and compared between the two groups. Results: The total effective rate in the treatment group within 2 hours (99%) was significantly higher than that in the control group (63%) (P<0.01). Conclusion: Pentoxyverine hydrochloride has a strong and long-lasting antispasmodic and analgesic effect and is worthy of clinical promotion as an alternative to atropine.

[0007] Existing research (Yin Rong, Wei Feng. Comparative Study of Clinical Efficacy of Pentoxyverine Hydrochloride and Phloroglucinol in the Treatment of Primary Dysmenorrhea, Chinese Journal of Hospital Drug Evaluation and Analysis, 2020, Vol. 6, No. 20) has shown that pentoxyverine hydrochloride and phloroglucinol are comparable in clinical efficacy in the treatment of primary dysmenorrhea. Methods: 120 patients with primary dysmenorrhea admitted to Chongqing Emergency Medical Center from January 2016 to December 2018 were selected and randomly divided into an observation group and a control group, with 60 patients in each group. Patients in the observation group received 1 mg of pentoxyverine hydrochloride intramuscularly, while patients in the control group received 80 mg of phloroglucinol intramuscularly. The visual analogue scale (VAS) scores, drug onset time, clinical efficacy, and adverse reactions were observed before and after medication in both groups. Conclusion: Pentoxyverine hydrochloride and phloroglucinol are safe and effective in treating primary dysmenorrhea. Pentoxyverine hydrochloride has a faster onset of action than phloroglucinol, while phloroglucinol has fewer adverse reactions than pentoxyverine hydrochloride.

[0008] Existing research (Wang Xiaopei. Effects of pre-injection of pentoxyverine hydrochloride on vital signs and adverse reactions in patients undergoing abdominal surgery, Chinese Journal of Rehabilitation Medicine, 2019, Vol. 11, No. 28) aims to observe the effects of pre-injection of pentoxyverine hydrochloride on vital signs and adverse reactions in patients undergoing abdominal surgery. Conclusion: Pre-injection of pentoxyverine hydrochloride in patients undergoing abdominal surgery can significantly reduce the impact on vital signs and is beneficial in reducing the incidence of adverse reactions.

[0009] Existing technology (Zhou Xinggen et al., Efficacy of pentoxyverine hydrochloride in the diagnosis and treatment of non-variceal upper gastrointestinal bleeding by emergency gastroscopy under intravenous anesthesia, Journal of Transportation Medicine, Vol. 6, No. 33, 2019) has shown the efficacy of pentoxyverine hydrochloride in the diagnosis and treatment of non-variceal upper gastrointestinal bleeding by emergency gastroscopy under intravenous anesthesia. Sixty patients with non-variceal upper gastrointestinal bleeding undergoing emergency gastroscopy and endoscopic hemostasis were randomly selected and divided into three groups (A, B, and C), with 20 patients in each group. Before anesthesia, patients were given intramuscular injections of pentoxyverine hydrochloride 0.5 mg (Group A), anisodamine 10 mg (Group B), and atropine 0.5 mg (Group C), respectively. Conclusion: For emergency gastroscopy under intravenous anesthesia to treat non-variceal upper gastrointestinal bleeding, pentoxyverine hydrochloride is a better choice than anisodamine and atropine in stabilizing heart rate, shortening hemostasis time, reducing anesthetic dosage, accelerating recovery, and alleviating postoperative abdominal pain, with fewer adverse reactions.

[0010] Modern technology (Liao Zhi, Xiao Hongtao. Clinical study on the treatment of primary dysmenorrhea with pentoxyverine hydrochloride tablets, Medical and Health Science and Technology R271.11) has shown that previous research, through the establishment of a rat model of primary dysmenorrhea, writhing scoring, and observation of uterine histopathological changes, indicated that pentoxyverine hydrochloride can effectively improve dysmenorrhea and improve uterine pathological changes. This study collected and recorded basic information on patients with primary dysmenorrhea, including duration of dysmenorrhea, severity of dysmenorrhea, need for drug relief, type and dosage of relieving drugs used, degree of relief, and pain scores. The clinical efficacy, pain scores, adverse reactions, and experimental data such as serum prostaglandins and β-endorphins of ibuprofen and pentoxyverine hydrochloride in treating primary dysmenorrhea were compared. This study focuses on the current situation of patients with primary dysmenorrhea, providing them with medical support for symptom relief, and exploring new options for the treatment of primary dysmenorrhea and new clinical uses of pentoxyverine hydrochloride.

[0011] Existing research (Liao Mengjie. Clinical efficacy of pentehyclidine hydrochloride in the treatment of primary dysmenorrhea, Master's thesis, University of Electronic Science and Technology of China) indicates that this prospective controlled clinical trial compared pentehyclidine hydrochloride (PHC) and ibuprofen in the treatment of primary dysmenorrhea (PD). Analysis of pain scores, serum prostaglandins, endorphins, and efficacy determined which drug had more definite efficacy and fewer side effects, exploring the application prospects of PHC in PD treatment and providing a safe and effective new approach for PD treatment. Conclusion: In terms of overall efficacy, PHC has a pain-relieving effect on PD, with efficacy comparable to ibuprofen. Regarding dysmenorrhea symptom scores, PHC not only relieves subjective pain but also reduces the severity and duration of accompanying symptoms in most PD patients. Compared with ibuprofen, it has better sedative and anti-anxiety effects. Regarding serum prostaglandin and β-endorphin levels, PHC can reduce serum prostaglandin levels and increase β-endorphin levels in PD patients, suggesting that endocrine factors are involved in the synergistic regulation of PHC's dysmenorrhea relief. In terms of side effects, PHC may cause dry mouth, sore throat, and reduced sweating, but these symptoms are relieved and recovered quickly, and have no impact on heart rate or other aspects, making it highly safe. For PD patients who do not respond to conventional drug treatment or have impaired liver or kidney function or gastrointestinal tract, PHC treatment can be chosen. This adds new drug options to the diagnosis and treatment of PD and also develops new pharmacological effects and clinical applications for PHC.

[0012] Existing research (Chen Shujie, Mo Zhengji, Liu Yi, Liu Ping. Antispasmodic effect of pentoxyverine hydrochloride on acetylcholine / clobeticol-induced small intestinal spasm in rabbits, West China Journal of Pharmaceutical Sciences, 2003, Vol. 05) has shown that pentoxyverine hydrochloride (PQN) administered intramuscularly and by gavage has an inhibitory effect on the in vivo small intestinal smooth muscle of anesthetized and conscious rabbits. Methods: Spastic contraction of the small intestinal smooth muscle in rabbits was induced by the cholinergic receptor agonist acetylcholine (ACh) and clobeticol, and then PQN was used to antagonize the effect, with atropine as a control. Conclusion: PQN can inhibit the in vivo spastic contraction of the small intestine in anesthetized and conscious rabbits induced by ACh and clobeticol.

[0013] Existing research (Liu Yi, Mo Zhengji, Chen Shujie, Guo Xi. Pharmacodynamic study of the antispasmodic effect of pentoxyverine hydrochloride on the stomach, China Pharmaceutical Industry Journal, 2003, No. 9) has shown that intramuscular injection and gavage administration of pentoxyverine hydrochloride (PQN) have inhibitory effects on the contraction of the stomach in anesthetized and conscious rabbits and isolated gastric strips in guinea pigs. The results indicate that PQN can inhibit the increase in gastric pressure induced by acetylcholine (Ach) and clobetacholine, antagonize the contractile effect of Ach on isolated gastric strips, and inhibit the spontaneous contraction of isolated gastric strips.

[0014] Existing research (Liu Ping, Mo Zhengji, Liu Yi, Yan Xiaoyan. Effects of pentoxyverine hydrochloride on isolated guinea pig bladder and in vivo rabbit bladder, West China Journal of Pharmaceutical Sciences, 2000, Vol. 3) has shown that pentoxyverine hydrochloride (IM and IG) has an inhibitory effect on the contractile function of anesthetized and conscious rabbit bladders in vivo and isolated guinea pig bladders. Methods: In vivo, a balloon was inserted into the rabbit bladder, and acetylcholine (ACh) was administered at multiple time points after IM and IG administration. Intravesical pressure was measured. In vitro, the maximum tension of spontaneous contraction and acetylcholine-induced contraction of isolated guinea pig bladder strips after pentoxyverine hydrochloride administration was measured, and the concentration of pentoxyverine hydrochloride required to inhibit 50% contraction was calculated. Results: Pentoxyverine hydrochloride inhibited the increase in intravesical pressure induced by ACh, antagonized the contractile effect of ACh on isolated bladder strips, and inhibited spontaneous contraction of isolated bladder strips. Conclusion: Pentoxyverine hydrochloride can effectively relieve bladder spasm.

[0015] Existing research (Yan Xiaoyan, Mo Zhengji, Liu Ping. Antispasmodic effect of pentoxyverine hydrochloride on isolated guinea pig ileum / colon, West China Journal of Pharmaceutical Sciences, 2005, Vol. 01) has shown that pentoxyverine hydrochloride (PHC) has an inhibitory effect on the contractile function of isolated guinea pig ileum / colon muscle strips. Methods: Isolated guinea pig ileum / colon strips were suspended in a McBurney bath. The maximum tension of spontaneous contraction and acetylcholine (Ach)-induced spastic contraction of the isolated muscle strips was measured after PHC administration. The concentration of PHC required to inhibit 5.0% contraction was calculated. Results: PHC significantly inhibited spontaneous contraction of isolated guinea pig ileum / colon muscle strips and significantly relaxed acetylcholine (Ach)-induced spastic contraction. Conclusion: PHC can effectively relieve the spastic state of isolated ileum / colon.

[0016] Existing research indicates that anticholinergic drugs are effective as antispasmodics in clinical practice, but they suffer from problems such as difficulty in controlling dosage and a high incidence of adverse reactions. Pentoxyverine hydrochloride is a novel selective anticholinergic drug. There have been some exploratory clinical studies on the use of pentoxyverine hydrochloride for smooth muscle spasm relief, with administration via injection. No oral formulations of pentoxyverine hydrochloride have yet been found for use in the field of smooth muscle spasm relief, thus failing to fully realize the clinical value of pentoxyverine hydrochloride as a novel anticholinergic drug. This invention fills this gap.

[0017] Compared with anticholinergic drugs such as atropine sulfate, pentoxyverine hydrochloride has significant advantages such as lower dosage, faster onset of action, longer duration of action, and lower incidence of adverse reactions.

[0018] The minimum effective dose of pentoxyverine hydrochloride can be as low as 0.1 mg per dose. Developing it into a solid dosage form presents significant challenges in ensuring the uniform dispersion of its main component within the excipients. Furthermore, different excipients can negatively impact the solubility, dispersion, and absorption of the main component. Currently, pentoxyverine hydrochloride injection has been approved for a shelf life of up to 5 years, demonstrating the high stability of its main component in water-based formulations. Therefore, there is ample evidence to support its long-term storage stability when developed into an oral liquid formulation. The development of pentoxyverine hydrochloride oral solution ensures the homogeneity and stability of the main component in each dose, playing a crucial role in guaranteeing clinical efficacy.

[0019] Penehyclidine hydrochloride, chemically known as 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxy)quinine cycloane hydrochloride, has the molecular formula C2. 20 H 29 NO2·HCl, molecular weight 351.92. Summary of the Invention

[0020] One of the objectives of this invention is to provide a new pharmaceutical formulation of the compound pentoxyverine hydrochloride, a new route of administration and clinical application, which greatly broadens the application field of the compound pentoxyverine hydrochloride and can give full play to its medical value.

[0021] Another objective of this invention is to provide a new anticholinergic drug that, unlike existing drugs, relieves smooth muscle spasms. This provides clinicians with a new, safer, and more effective drug option for treating biliary colic, gastric colic, renal colic, irritable bowel colic, dysmenorrhea, and other diseases. Because pentoxyverine hydrochloride has a very clear smooth muscle spasm-relieving effect, it can be used in gastroscopy, colonoscopy, laparoscopy and related surgeries, gallbladder surgery, myomectomy, curettage, and other procedures. By exerting its smooth muscle spasm-relieving effect, it can reduce the difficulty and trauma of examinations or surgeries, alleviate patient suffering, and reduce the incidence of postoperative nausea and vomiting.

[0022] The pentoxyverine hydrochloride described in this invention has the therapeutic effect of relieving smooth muscle spasms, which has been fully verified through animal pharmacodynamic studies and various clinical exploratory studies.

[0023] The present invention is implemented by preparing the pentoxyverine hydrochloride compound into an oral liquid formulation using a pharmaceutical method for preparing oral liquid formulations. The specific drug formulation and preparation method are described in the examples.

[0024] The pharmaceutical preparation described in this invention is an oral liquid preparation made by means of pentoxyverine hydrochloride as the main component, with the addition of pharmaceutically acceptable auxiliary components, through a formulation process.

[0025] Pharmaceutically acceptable adjuncts include solvents, pH adjusters, flavoring agents, preservatives, etc.

[0026] The solvent refers to the solvent used to dissolve or dilute the drug components, thereby achieving a certain drug concentration in the solvent, such as water.

[0027] The pH adjuster refers to the agent that stabilizes the pH of the solution within a certain range by adding an appropriate proportion of acidic or alkaline substances. Examples include hydrochloric acid, sodium hydroxide, sodium bicarbonate, phosphate, citric acid, and boric acid.

[0028] The flavoring agent mentioned refers to sweeteners such as white sugar, steviol glycosides, sucralose, and aspartame.

[0029] The preservatives are sodium benzoate, parabens, potassium sorbate, etc.

[0030] The volume ratio of pentoxyverine hydrochloride compound to auxiliary components in the drug of the present invention is 1:5000 to 1:100000, preferably 1:50000 to 1:100000.

[0031] The content of the active ingredient in the pharmaceutical preparation, calculated based on pentoxyverine hydrochloride, is 0.01 mg / ml, 0.02 mg / ml, 0.05 mg / ml, 0.1 mg / ml, or 0.2 mg / ml, respectively.

[0032] The single-dose content of the active ingredient in the pharmaceutical preparation, calculated based on pentoxyverine hydrochloride, is 0.1 mg / vial, 0.2 mg / vial, 0.5 mg / vial, 1.0 mg / vial, or 2.0 mg / vial.

[0033] The pharmaceutical preparation of this invention mainly includes the following key process steps: pentoxyverine hydrochloride is dissolved, pH value is adjusted, flavoring agent and preservative are added, volume is adjusted, stirring and mixing are performed, filtration is carried out, and the product is packaged.

[0034] Compared with the prior art, the advantages of the present invention are as follows: 1. Pentoxyverine hydrochloride can selectively act on M1 and M3 receptor subtypes. Pharmacodynamic tests have shown that pentoxyverine hydrochloride has a very significant pacing and antispasmodic effect. At the same time, because it does not act on M2 receptors, it can overcome the heart rate acceleration effect inherent in other non-receptor-selective anticholinergic drugs, such as scopolamine and atropine, which can cause users to have an increased heart rate and palpitations.

[0035] 2. Pentoxyverine hydrochloride has a rapid onset of action and a long duration of action after administration. Studies have shown that pentoxyverine hydrochloride can be detected in the blood within 5 minutes of administration, indicating that its absorption is very rapid. At the same time, pentoxyverine hydrochloride has a half-life of 10.35 hours, which provides a long duration of action and reduces the need for frequent administration, thus reducing the inconvenience for patients.

[0036] 3. Pentoxyverine hydrochloride requires a smaller dosage; a single dose of 0.1 mg is sufficient to take effect. Compared to the conventional intramuscular dose of 1.0 mg already used in clinical practice, the dosage is reduced by 1 / 10, which greatly reduces the incidence of adverse reactions. Detailed Implementation

[0037] The present invention will be further described in detail below with reference to the embodiments, but it should not be construed as the technical solution of the present invention being limited to the following embodiments.

[0038] Example 1: Preparation method for a 0.01 mg / ml solution. Add 90 L of purified water to a mixing tank or container. Dissolve 1 g of pentoxyverine hydrochloride in an appropriate amount of purified water, then add the solution to the mixing tank and stir until homogeneous. Adjust the pH to approximately 6.0 with hydrochloric acid or sodium hydroxide solution. Add 10 g of aspartame and stir until dissolved. Add 100 g of paraben and stir until dissolved. Add water to a final volume of 100 L, stir until homogeneous, filter, and dispense into sterilized oral liquid packaging materials. Single dose: 10 ml / vial. Administration: Oral administration. For use before medical examinations or surgery to prevent smooth muscle spasms. It is recommended to take this product 30 minutes before the examination or surgery.

[0039] Example 2: Preparation method for a 0.02 mg / ml solution. Add 90 L of purified water to a mixing tank or container. Dissolve 2 g of pentoxyverine hydrochloride in an appropriate amount of purified water, then add the solution to the mixing tank and stir until homogeneous. Adjust the pH to approximately 6.0 with hydrochloric acid or sodium hydroxide solution. Add 10 g of aspartame and stir until dissolved. Add 100 g of paraben and stir until dissolved. Add water to a final volume of 100 L, stir until homogeneous, filter, and dispense into sterilized oral liquid packaging materials. Single dose: 10 ml / vial. Administration: Oral administration. For use before medical examinations or surgery to prevent smooth muscle spasms. It is recommended to take this product 30 minutes before the examination or surgery.

[0040] Preparation method of 0.05 mg / ml solution as described in Section 3: Add 90 L of purified water to a mixing tank or container. Dissolve 5 g of pentoxyverine hydrochloride raw material in an appropriate amount of purified water, then add it to the mixing tank and stir well. Adjust the pH to approximately 6.0 with hydrochloric acid solution or sodium hydroxide solution. Add 10 g of aspartame and stir until dissolved. Add 100 g of paraben and stir until dissolved. Add water to a final volume of 100 L, stir well, filter, and dispense into sterilized oral liquid packaging materials. Single dose: 10 ml / vial. Administration: Oral administration. For use before medical examinations or surgeries to prevent smooth muscle spasms. It is recommended to take this product 30 minutes before the examination or surgery.

[0041] Preparation method of 0.1 mg / ml solution as described in Section 4: Add 90 L of purified water to a mixing tank or container. Dissolve 10 g of pentoxyverine hydrochloride raw material in an appropriate amount of purified water, then add it to the mixing tank and stir well. Adjust the pH to approximately 6.0 with hydrochloric acid solution or sodium hydroxide solution. Add 10 g of aspartame and stir until dissolved. Add 100 g of paraben and stir until dissolved. Add water to a final volume of 100 L, stir well, filter, and dispense into sterilized oral liquid packaging materials. Single dose: 10 ml / vial. Administration: Oral administration. For use before medical examinations or surgeries to prevent smooth muscle spasms. It is recommended to take this product 30 minutes before the examination or surgery.

[0042] Preparation method of 0.01 mg / ml solution as described in Section 5: Add 90 L of purified water to a mixing tank or container. Dissolve 1 g of pentoxyverine hydrochloride raw material in an appropriate amount of purified water, then add it to the mixing tank and stir well. Adjust the pH to approximately 6.0 with phosphate buffer solution. Add 10 g of aspartame and stir until dissolved. Add 100 g of paraben and stir until dissolved. Add water to a final volume of 100 L, stir well, filter, and dispense into sterilized oral liquid packaging materials. Single dose: 10 ml / vial. Administration: Oral administration. For use before medical examinations or surgeries to prevent smooth muscle spasms. It is recommended to take this product 30 minutes before the examination or surgery.

[0043] Preparation method of the 0.02 mg / ml solution as described in Section 6: Add 90 L of purified water to a mixing tank or container. Dissolve 2 g of pentoxyverine hydrochloride raw material in an appropriate amount of purified water, then add it to the mixing tank and stir well. Adjust the pH to approximately 6.0 with phosphate buffer solution. Add 10 g of aspartame and stir until dissolved. Add 100 g of paraben and stir until dissolved. Add water to a final volume of 100 L, stir well, filter, and dispense into sterilized oral liquid packaging materials. Single dose: 10 ml / vial. Administration: Oral administration. For use before medical examinations or surgeries to prevent smooth muscle spasms. It is recommended to take this product 30 minutes before the examination or surgery.

[0044] Preparation method of 0.05 mg / ml solution as described in Section 7: Add 90 L of purified water to a mixing tank or container. Dissolve 5 g of pentoxyverine hydrochloride raw material in an appropriate amount of purified water, then add it to the mixing tank and stir well. Adjust the pH to approximately 6.0 with phosphate buffer solution. Add 10 g of aspartame and stir until dissolved. Add 100 g of paraben and stir until dissolved. Add water to a final volume of 100 L, stir well, filter, and dispense into sterilized oral liquid packaging materials. Single dose: 10 ml / vial. Administration: Oral administration. For use before medical examinations or surgeries to prevent smooth muscle spasms. It is recommended to take this product 30 minutes before the examination or surgery.

[0045] Preparation method of 0.1 mg / ml solution as described in Section 8: Add 90 L of purified water to a mixing tank or container. Dissolve 10 g of pentoxyverine hydrochloride raw material in an appropriate amount of purified water, then add it to the mixing tank and stir well. Adjust the pH to approximately 6.0 with phosphate buffer solution. Add 10 g of aspartame and stir until dissolved. Add 100 g of paraben and stir until dissolved. Add water to a final volume of 100 L, stir well, filter, and dispense into sterilized oral liquid packaging materials. Single dose: 10 ml / vial. Administration: Oral administration. For use before medical examinations or surgeries to prevent smooth muscle spasms. It is recommended to take this product 30 minutes before the examination or surgery.

Claims

1. A method for preparing a new formulation of pentoxyverine hydrochloride and its application.

2. The novel dosage form of pentoxyverine hydrochloride according to claim 1 refers to an oral liquid preparation, characterized in that: The oral liquid formulation is an oral solution prepared by a pharmaceutical process using pentoxyverine hydrochloride as the main component and pharmaceutically acceptable auxiliary components.

3. The preparation method and application of the novel formulation of pentoxyverine hydrochloride according to claim 1, characterized in that: The oral liquid preparation, which is mainly composed of pentoxyverine hydrochloride, is administered orally in clinical practice.

4. The preparation method and application of the novel dosage form of pentoxyverine hydrochloride according to claim 1, wherein the weight-volume ratio of the pentoxyverine hydrochloride compound to the auxiliary components in the drug is 1:5000 to 1:100000.

5. The preparation method and application of the novel formulation of pentoxyverine hydrochloride according to claim 1 or 2, characterized in that... The packaging materials that come into direct contact with the medicine can be glass bottles and their kits, plastic bottles, composite aluminum foil bags, and other commonly used packaging materials for oral liquid preparations.

6. The preparation method and application of the novel formulation of pentoxyverine hydrochloride according to claim 1 or 2, characterized in that... The new dosage form made with pentoxyverine hydrochloride as the main component has new clinical applications for biliary colic, gastric colic, renal colic, intestinal colic caused by intestinal stress, and dysmenorrhea caused by smooth muscle spasm due to various reasons.

7. The preparation method and application of the novel formulation of pentoxyverine hydrochloride according to claim 1 or 2, characterized in that... The new dosage form made with pentoxyverine hydrochloride as the main component can also be used in new clinical applications such as gastroscopy, colonoscopy, laparoscopy and related surgeries, gallbladder surgery, myomectomy, and curettage.

8. The preparation method and application of the novel formulation of pentoxyverine hydrochloride according to claim 2 or 4, characterized in that: Pharmaceutically acceptable adjuncts include solvents, pH adjusters, flavoring agents, and preservatives.

9. The preparation method and application of the novel formulation of pentoxyverine hydrochloride according to claim 2 or 4, characterized in that: The solvent is water.

10. The preparation method of the novel formulation of pentoxyverine hydrochloride according to claim 2 or 4 and its application, characterized in that: The pH adjuster refers to hydrochloric acid, sodium hydroxide, sodium bicarbonate, phosphate, citric acid, boric acid, etc.

11. The preparation method and application of the novel formulation of pentoxyverine hydrochloride according to claim 2 or 4, characterized in that: The flavoring agents mentioned refer to sweeteners such as white sugar, steviol glycosides, sucralose, and aspartame.

12. The preparation method and application of the novel formulation of pentoxyverine hydrochloride according to claim 2 or 4, characterized in that: The preservatives mentioned are sodium benzoate, parabens, potassium sorbate, etc.

13. The preparation method of the novel formulation of pentoxyverine hydrochloride according to claim 2 or 4 and its application, characterized in that: The content of the active ingredient in the pharmaceutical preparation, calculated based on pentoxyverine hydrochloride, is 0.01 mg / ml, 0.02 mg / ml, 0.05 mg / ml, 0.1 mg / ml, or 0.2 mg / ml, respectively.

14. The preparation method of the novel formulation of pentoxyverine hydrochloride according to claim 2 or 4 and its application, characterized in that: The single-dose content of the active ingredient in the pharmaceutical preparation, calculated based on pentoxyverine hydrochloride, is 0.1 mg / vial, 0.2 mg / vial, 0.5 mg / vial, 1.0 mg / vial, or 2.0 mg / vial.