WO2018161890A1 - 小檗碱在制备治疗急性软组织损伤的药物中的应用 - Google Patents
小檗碱在制备治疗急性软组织损伤的药物中的应用 Download PDFInfo
- Publication number
- WO2018161890A1 WO2018161890A1 PCT/CN2018/078132 CN2018078132W WO2018161890A1 WO 2018161890 A1 WO2018161890 A1 WO 2018161890A1 CN 2018078132 W CN2018078132 W CN 2018078132W WO 2018161890 A1 WO2018161890 A1 WO 2018161890A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- berberine
- soft tissue
- tissue injury
- acute soft
- effect
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
Definitions
- the invention relates to the technical field of natural medicines, in particular to the application of berberine in the preparation of a medicament for treating acute soft tissue injury.
- Berberine also known as berberine, is an important alkaloid that can be extracted from traditional Chinese medicines (such as berberine, cork, three needles, etc.) with a long history in China. It is widely distributed in the plant kingdom, and it is found in about 10 families of 4 families. The clinical application is mainly the hydrochloride and sulfate of this product. China's current synthesis method is mass produced. Berberine is a broad-spectrum antibacterial agent and has the effect of enhancing white blood cells to phagocytose Staphylococcus aureus.
- dysentery bacilli tubercle bacilli
- pneumococcal bacteria typhoid bacillus
- diphtheria bacilli diphtheria bacilli.
- dysentery bacilli tubercle bacilli
- pneumococcal bacteria typhoid bacillus
- diphtheria bacilli diphtheria bacilli.
- Acute soft tissue injury refers to a series of acute contusions or (and) lacerations in the body's motor system and tissues other than the skin below the skin, including muscles, ligaments, fascia, tendons, synovium, fat, joint capsules, etc. Acute injury to different conditions of peripheral nerves and blood vessels. These tissues are affected by external or intrinsic different injury factors, causing damage to the tissue due to acute disruption of the tissue and temporary disturbances in the physiological function of the tissue. Acute soft tissue injury is generally affected by external structural stress. When the stress reaches a certain intensity and exceeds the load of the soft tissue, it can induce damage and produce symptoms. The main manifestations are swelling and pain. In the acute phase, local oozing, edema, and severe pain.
- muscle, tendon adhesion, ischemic contracture, inflammation around the joints, and even joint stiffness may occur. It can usually be treated by analgesia, physiotherapy, braking, Chinese medicine, blood circulation and other methods.
- Local cold compress within 24 hours of injury can make the skin vasoconstriction, tissue edema subsided, and play a role in stopping bleeding and swelling.
- For the soft tissue contusion treatment with early application of the method has a very good effect. Patients often have immediate swelling and pain relief after application, and the bandage fixation during application can not only maintain the joint of the joint in the injured ligament, temporarily limit the movement of the limb, but also facilitate the repair of the damaged ligament, thereby shortening the treatment time.
- Berberine has a good anti-inflammatory and anti-tumor effect, can effectively reduce the inflammatory exudate of patients with acute soft tissue injury, and relieve pain symptoms.
- berberine in the preparation of a medicament for treating acute soft tissue injury
- the molecular formula of the berberine is C20H18N04
- the molecular weight is 235.32
- the CAS accession number is 2086-83-1.
- the berberines of the present invention can be extracted from Coptis chinensis and Phellodendron chinense, and can also be obtained by synthetic or other methods.
- Berberine can be obtained commercially, and there are a large number of reports on its extraction or synthesis methods; the berberine is derived from the dried rhizome of Ranunculaceae, Coptis chinensis, Coptis or Coptis, and the above three are respectively called “flavor” ",” “Yalian”, “Yunlian”; the cork is derived from the dry bark of the Phyllostachys pubescens plant, known as “Chuanhuangbai”; the dry bark of the sassafras scutellariae, known as “Guan Huangbai” ".
- the main clinical manifestations of acute soft tissue injury are pain and swelling, and there is no literature report on the treatment of acute soft tissue injury.
- Berberine has a good anti-inflammatory and anti-tumor effect, can effectively reduce the inflammatory exudate of patients with acute soft tissue injury, relieve pain symptoms, has a good therapeutic effect on acute soft tissue injury, does not contain any toxic and harmful ingredients, Safe and effective.
- the content of berberine in the drug is 1% to 99.5% by weight, and the rest is a pharmaceutically acceptable auxiliary;
- the auxiliary material may be a preservative, a solvent, an emulsifier or a penetration enhancer. Conventional auxiliary substances.
- the medicament is a dosage form that can be prepared by conventional pharmaceutical equipment.
- the dosage form is a lotion, a spray, an ointment, and a gel.
- the same drug, different dosage forms is suitable for different stages of disease development and development. Different dosage forms can be correctly selected according to the symptoms and characteristics of different stages of the disease, such as skin diseases.
- the solution is mostly wet. Applying, can play an anti-inflammatory effect; those who have exudate, first apply wet solution with solution, then use oil; when the skin lesion is in the subacute phase, the redness and swelling are reduced, the exudate is reduced, and the lotion can be selected as appropriate to exert its anti-inflammatory effect. Itching, astringent, and protective effects; thickening of chronic skin lesions, the use of ointments or gels, its penetrating power, long-lasting effect, and the role of lubrication and skin care.
- the content of berberine in the drug is 99.5% by weight percentage, which is the optimal content, and the pharmaceutical composition prepared by using the content has superior therapeutic effect on acute soft tissue injury. .
- berberine has various pharmacological effects such as anti-microbial, anti-arrhythmia, hypolipidemic, hypoglycemic, anti-inflammatory, anti-tumor, sedative and hypnotic.
- Berberine is administered through the skin at a high concentration, directly to the disease site. In addition to its local effects, it can also enter the blood circulation through the skin to exert a systemic effect, effectively alleviating the pain and swelling symptoms of the patient.
- the stratum corneum of the skin also has a storage function, which makes the blood drug concentration curve stable, and has the advantage that it is unique beyond the general administration method.
- the invention provides a novel Chinese medicine monomer component for treating acute soft tissue injury, which has clear functions, no toxic and side effects, and broadens the range of berberine for preventing and treating diseases.
- Formulation 10 kg of berberine hydrochloride (active ingredient), 1 kg of hydroxyphenylethyl ester (preservative), 2 kg of sodium benzoate (preservative), and an appropriate amount of distilled water (solvent).
- Preparation method the active ingredient and other auxiliary materials are dissolved in distilled water, and the volume is adjusted to 1000 L, and the mixture is sterilized and obtained.
- Formulation 11 kg of berberine hydrochloride (active ingredient), 1 kg of hydroxyphenylethyl ester (preservative), 2 kg of sodium benzoate (preservative), and an appropriate amount of distilled water (solvent).
- Preparation method the active ingredient and other auxiliary materials are dissolved in distilled water, and the volume is adjusted to 1000 L, and the mixture is sterilized and obtained.
- Formulation 13 kg of berberine hydrochloride (active ingredient), 1 kg of hydroxyphenylethyl ester (preservative), 2 kg of sodium benzoate (preservative), and an appropriate amount of distilled water (solvent).
- Preparation method the active ingredient and other auxiliary materials are dissolved in distilled water, and the volume is adjusted to 1000 L, and the mixture is sterilized and obtained.
- Formulation 10 kg of berberine hydrochloride (active ingredient), 1 kg of borneol (permeation enhancer), and appropriate amount of distilled water (solvent).
- Preparation method the active ingredient and other auxiliary materials (the pre-treatment can be pre-treated) are dissolved in distilled water, the volume is adjusted to 1000 L, and the mixture is dispensed to a sprayer and sterilized.
- Formulation 1.0 kg of berberine hydrochloride (active ingredient), 2.4 kg of stearic acid (matrix), 1.4 kg of glyceryl monostearate (matrix), 0.2 kg of white petrolatum (matrix), 1.0 kg of lanolin (matrix), Liquid paraffin (matrix) 1.2kg, Tween (emulsifier) 800.08kg, distilled water (solvent) appropriate amount.
- Preparation method taking stearic acid, glyceryl monostearate, white petrolatum and liquid paraffin in a small beaker, heating to about 80 ° C on a water bath, stirring to melt (oil phase). Another Tween 80 and a calculated amount of distilled water were placed in another small beaker, heated to about 80 ° C on a water bath, and stirred evenly (aqueous phase). At the same temperature, the aqueous phase was added to the oil phase in a fine stream, and continuously stirred in a water bath on a milky white semi-solid state, and then stirred at room temperature until near condensation. The berberine hydrochloride was placed on an ointment plate and a mortar, and the prepared O/W emulsifier matrix was added in portions, and the solution was obtained.
- Formulation 1.0 kg of berberine hydrochloride (active ingredient), 1.2 kg of sodium carboxymethylcellulose (matrix), 2.0 kg of glycerin (humectant), 0.1 kg of sodium benzoate (preservative), and an appropriate amount of distilled water.
- the preparation method comprises the following steps: taking sodium hydroxymethylcellulose to be ground, adding glycerin to grind well, and then adding an aqueous solution containing sodium benzoate and berberine hydrochloride while being uniformly ground, and then swelling and then homogenizing to obtain.
- the analgesic effect of berberine was observed by a mouse thermal stimulation test, a mouse acetic acid writhing test, and a mouse formaldehyde pain test.
- mice in Kunming were selected from qualified female mice with a basic pain threshold of 5-30s. They were randomly divided into 5 groups: blank control group, fustatin positive control group and berberine high concentration group. 10 mg/ml), medium concentration group (5 mg/ml), low concentration group (2.5 mg/ml), 13 rats in each group. The mice were placed on a metal plate preheated to about 55 ° C, and the hind paws were used as indicators of pain reflection to observe changes in pain threshold before and after administration. The corresponding drugs were applied to the feet every day for 5 days, and the pain threshold of the mice was measured at 0.5 h, 1 h, 1.5 h, 2 h after the last administration.
- mice weighing 18-22g, were randomly divided into 5 groups: blank control group, Futalin positive control group, berberine high concentration group (10mg/ml), medium concentration group (5mg/ml), low concentration group. (2.5 mg/ml), 15 per group.
- the corresponding drugs were applied to the abdomen every day for 5 days. After the last administration for 60 minutes, each group of mice was intraperitoneally injected with 0.7% acetic acid 0.1 ml/10 g, and the number of writhing reactions of the mice within 15 min was observed.
- mice male and female, weighing 18-22g, were randomly divided into 5 groups, which were blank control group, Futalin positive control group, berberine high concentration group (10mg/ml) and medium concentration group (5mg). /ml), low concentration group (2.5mg/ml), 14 rats in each group, continuous administration for 5 days, 60 minutes after the last administration, each group of animals was subcutaneously injected with 2.5% formaldehyde solution (50ul/ in the left hind foot) with a micro syringe. Immediately after being placed in a large flat glass container, the cumulative time of the hind paws of the mice was observed (observation time was 0-10 min and 15-30 min after injection).
- Berberine has no obvious analgesic effect on the heat-induced pain test in mice, and has obvious analgesic effect on the pain caused by formaldehyde and acetic acid. It shows that berberine has a certain analgesic effect and has obvious effects on pain caused by inflammation.
- mice were randomly divided into 5 groups: blank control group, Futalin positive control group, berberine high concentration group (10 mg/ml), medium concentration group (5 mg/ml), low concentration group (2.5 mg/ml), each group 15 only.
- xylene was evenly applied to both sides of the left auricle of the mouse, and the right ear was not coated as a normal ear.
- the mouse was sacrificed from the cervical vertebra, and the left and right were cut along the edge of the auricle. Both ears, using a hole punch with a diameter of 6 mm, remove the round ears on the same part of the left and right ears, immediately weighed with an analytical balance, calculate the degree of ear swelling, and calculate the inhibition rate of ear swelling.
- mice half male and half female, weighing 18-22g, were randomly divided into 5 groups, blank control group, positive control group, berberine high concentration group (10mg/ml), medium concentration group (5mg/ml), low. Concentration group (2.5 mg/ml), 12 in each group.
- the above groups of mice were administered continuously for 7 days, and 60 minutes after the 7th day of administration, the mice were injected with 0.5% Evans Blue (0.1 ml/10 g) in the tail vein, followed by intraperitoneal injection of 0.6% acetic acid (0.1 ml/10 g). After 20 min, the mice were sacrificed by dislocation.
- the peritoneal cavity of each mouse was washed with 6 ml of physiological saline, the peritoneal fluid was aspirated, centrifuged at 3000 rpm for 15 min, and the supernatant was taken and the 0D value was measured at 590 nm on an ultraviolet spectrophotometer.
- Berberine has a significant inhibitory effect on ear swelling caused by xylene and an increase in capillary permeability caused by acetic acid, indicating that berberine has an anti-inflammatory effect.
- This part of the experiment is to observe the clinical efficacy of the drug of the present invention. Through the symptoms, signs and laboratory tests of acute soft tissue injury, the therapeutic effect of berberine was observed.
- Berberine can be used to treat acute soft tissue damage. Compared with Futalin, berberine has a quick onset, good curative effect and more clinical advantages.
- the berberine of the present invention has a good anti-inflammatory and swelling effect, and can effectively reduce the inflammatory exudate of patients with acute soft tissue injury and relieve pain symptoms.
- the berberine of the invention has various pharmacological effects such as anti-microbial, anti-arrhythmia, hypolipidemic, hypoglycemic, anti-inflammatory, anti-tumor, sedative and hypnotic.
- Berberine is administered through the skin at a high concentration, directly to the disease site. In addition to its local effects, it can also enter the blood circulation through the skin to exert a systemic effect, effectively alleviating the pain and swelling symptoms of the patient.
- the stratum corneum of the skin also has a storage function, which makes the blood drug concentration curve stable, and has the advantage that it is unique beyond the general administration method.
- mice thermal stimulation test mouse acetic acid writhing test, mouse formaldehyde pain test, mouse xylene ear swelling test, mouse capillary permeability test, the traditional Chinese medicine monomer component berberine has anti-inflammatory, town
- the pain effect is proved by clinical examples to have the effect of treating acute soft tissue injury.
- the invention provides a new medicine for the treatment of acute soft tissue damage, which has clear functions, no toxic and side effects, broadens the scope of berberine to prevent and treat diseases, and has a promising market prospect.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
小檗碱在制备治疗急性软组织损伤的药物中的应用，所述药物由小檗碱和药学上可接受的辅料组成。
Description
本发明涉及天然药物的技术领域，尤其涉及小檗碱在制备治疗急性软组织损伤的药物中的应用。
小檗碱，又称黄连素，是一种重要的生物碱，在我国应用历史悠久的中药(如黄连、黄柏、三颗针等)中都可以提取获得。在植物界中分布较广，大约有4个科10个属内发现有本品存在。临床应用主要为本品的盐酸盐和硫酸盐。我国现用合成法大量生产。小檗碱为广谱抗菌剂，并有加强白细胞吞噬金黄色葡萄球菌的作用，能对抗病原微生物，对多种细菌如痢疾杆菌、结核杆菌、肺炎球菌、伤寒杆菌及白喉杆菌等都有抑制作用。其中，对痢疾杆菌作用最强，常用来治疗细菌性胃肠炎、痢疾等消化道疾病。除此之外，具有降低血压及扩张冠状动脉的作用，对心脏有双相作用，小剂量兴奋，大剂量呈抑制状态；具有抗胆碱酯酶、增强乙酰胆碱的作用；有强大的抗箭毒作用；对血管平滑肌呈抑制作用，而对子宫、膀胱、支气管、胃肠平滑肌则呈兴奋作用。
急性软组织损伤系指人体运动系统、皮肤以下骨骼之外的组织所发生的一系列急性挫伤或(和)裂伤，包括肌肉、韧带、筋膜、肌腱、滑膜、脂肪、关节囊等组织以及周围神经、血管的不同情况的急性损伤。这些组织受到外来或内在的不同致伤因素的作用，造成组织急性破坏和组织生理功能的暂时紊乱而产生损伤。急性软组织损伤一般是受外来的结构应力的作用，当应力作用达到一定的强度超过软组织承受负荷，即能诱发损伤，产生症状，以肿胀、疼痛为主要表现。急性期，局部渗血、水肿，疼痛剧烈。晚期可能出现肌肉、肌腱的粘 连、缺血性挛缩，关节周围炎，甚至引起关节僵直。通常可以通过镇痛、理疗、制动、中成药活血化淤等方法治疗。在受伤24小时内局部冷敷可以使皮毛血管收缩，组织水肿消退，起到止血消肿止痛的作用。对于软组织挫伤采用早期敷药方法治疗，有着非常好的疗效。患者往往在敷药后就能即时消肿止痛，敷药时的绷带固定，不仅能保持关节于受伤韧带松弛的位置，暂时限制肢体活动，还有利于损伤韧带的修复，从而缩短了治疗时间。
目前，尚无文献报道小檗碱可用于治疗急性软组织损伤，经检索，没有公开小檗碱用于治疗急性软组织损伤的专利文献，也没有将小檗碱作为治疗急性软组织损伤药物使用的制剂上市。
发明内容
本发明的目的在于针对现有技术中的不足之处，提供小檗碱在制备治疗急性软组织损伤的药物中的应用。小檗碱具有良好的抗炎消肿作用，可以有效的减少急性软组织损伤患者的炎症渗出液，缓解疼痛症状。
为达此目的，本发明采用以下技术方案：
小檗碱在制备治疗急性软组织损伤的药物中的应用，所述小檗碱的分子式为C20H18N04，分子量是235.32，CAS登录号为2086-83-1。本发明所述的小檗碱可以从黄连、黄柏中提取得到，也可以由合成或其他方法制得。小檗碱可以通过商业购买获得，其提取或合成方法也有大量的文献报道；所述的黄连来源于毛茛科植物黄连、三角叶黄连或云连的干燥根茎，以上三种分别习称“味连”、“雅连”、“云连”；所述的黄柏来源于芸香科植物黄皮树的干燥树皮，习称“川黄柏”；芸香科植物黄檗的干燥树皮，习称“关黄柏”。急性软组织损伤的主要临床表现为疼痛、肿胀，尚无有关治疗急性软组织损伤的文献报道。
小檗碱具有良好的抗炎消肿作用，可以有效的减少急性软组织损伤患者的炎症渗出液，缓解疼痛症状，针对于急性软组织损伤有很好的治疗效果，不含任何有毒有害成分，既安全又有效。
更进一步地说明，按重量百分数计算，所述的药物中小檗碱的含量为1％～99.5％，其余为药学上可以接受的辅料；辅料可为防腐剂、溶剂、乳化剂或促渗剂等常规辅助物质。
更进一步地说明，所述的药物是常规制药设备可以制得的剂型。
更进一步地说明，所述的剂型为洗剂、喷雾剂、软膏剂和凝胶剂。同一药物，剂型不同，适用于疾病的发生发展阶段不同，不同剂型可根据疾病不同时期的症状和特点正确选用，如皮肤病，一般急性期局部有红肿、水疱、糜烂时，多选用溶液剂湿敷，可起到消炎作用；有渗液者，先用溶液剂湿敷，后用油剂；皮损处于亚急性期时，红肿减轻，渗液减少，可酌情选用洗剂，以发挥其消炎、止痒、收敛和保护作用；慢性期皮损增厚，多用软膏剂或凝胶剂，其穿透力强，作用持久，且有润滑护肤作用。
更进一步地说明，按重量百分数计算，所述的药物中小檗碱的含量为99.5％，此含量为最优含量，采用该含量所制备成的药物组合物在急性软组织损伤具有更优异的治疗效果。
本发明的有益效果：小檗碱具有抗微生物、抗心律失常、降血脂、降血糖、抗炎、抗肿瘤、镇静催眠等多种药理作用。小檗碱经皮肤给药浓度高，直达病所，除了起局部作用外，还可通过皮肤进人血液循环，发挥全身作用，有效缓解患者的疼痛、肿胀症状。另外，皮肤角质层还有贮存作用，使血药浓度曲线平稳，有超越一般给药方法独特的优点。通过小鼠热刺激试验、小鼠醋酸扭体试验、小鼠甲醛致痛试验、小鼠二甲苯耳肿胀试验、小鼠毛细血管通透性试验 证明中药单体成分小檗碱具有抗炎、镇痛功效，通过临床实例证明其具有治疗急性软组织损伤的作用。本发明为治疗急性软组织损伤提供一种中药单体成分新药，其功能明确、无毒副作用，同时拓宽了小檗碱防治疾病的范围。
下面通过具体实施例来对本发明方案进行详细说明。本领域技术人员应当理解，下列实施为优选实施例，其仅对本发明方案进行解释说明，而且其中可能会有对公知技术的适当省略，本领域技术人员应结合公知技术与实施例的说明，对本发明进行理解。
实施例1-洗剂的制备
配方：盐酸小檗碱(活性成分)10kg，羟苯乙酯(防腐剂)1kg，苯甲酸钠(防腐剂)2kg，蒸馏水适量(溶剂)。
制备方法：将活性成分和其它辅料溶解于蒸馏水中，定容至1000L，分装，灭菌，即得。
使用方法：纱布或棉签蘸取药液，清洗或湿敷患处，一日2次。
实施例2-洗剂的制备
配方：盐酸小檗碱(活性成分)11kg，羟苯乙酯(防腐剂)1kg，苯甲酸钠(防腐剂)2kg，蒸馏水适量(溶剂)。
制备方法：将活性成分和其它辅料溶解于蒸馏水中，定容至1000L，分装，灭菌，即得。
使用方法：纱布或棉签蘸取药液，清洗或湿敷患处，一日2次。
实施例3-洗剂的制备
配方：盐酸小檗碱(活性成分)13kg，羟苯乙酯(防腐剂)1kg，苯甲酸钠(防腐剂)2kg，蒸馏水适量(溶剂)。
制备方法：将活性成分和其它辅料溶解于蒸馏水中，定容至1000L，分装，灭菌，即得。
使用方法：纱布或棉签蘸取药液，清洗或湿敷患处，一日2次。
实施例4-喷雾剂的制备
配方：盐酸小檗碱(活性成分)10kg，冰片(促渗剂)1kg，蒸馏水(溶剂)适量。
制备方法：将活性成分和其它辅料(辅料可预先处理)溶解于蒸馏水中，定容至1000L，分装至喷雾器，灭菌，即得。
使用方法：均匀喷敷患处，一日2次。
实施例5-软膏剂的制备
配方：盐酸小檗碱(活性成分)1.0kg，硬脂酸(基质)2.4kg，单硬脂酸甘油脂(基质)1.4kg，白凡士林(基质)0.2kg，羊毛脂(基质)1.0kg，液体石蜡(基质)1.2kg，吐温(乳化剂)800.08kg，蒸馏水(溶剂)适量。
制备方法：取硬脂酸、单硬脂酸甘油脂、白凡士林和液体石蜡置小烧杯中，于水浴上加热至80℃左右，搅拌使熔化(油相)。另取吐温80和计算量蒸馏水置另一个小烧杯，于水浴上加热至约80℃，搅拌均匀(水相)。在同温下，将水相以细流加到油相中，并于水浴上不断顺方向搅拌成乳白色半固体状，再在室温下搅拌至近冷凝。取盐酸小檗碱置于软膏板上和研钵中，分次加入制得的O/W型乳化剂基质，研匀即得。
使用方法：均匀涂抹患处，一日2次。
实施例6-凝胶剂的制备
配方：盐酸小檗碱(活性成分)1.0kg，羟甲基纤维素钠(基质)1.2kg，甘油(保湿剂)2.0kg，苯甲酸钠(防腐剂)0.1kg，蒸馏水适量。
制备方法：取羟甲基纤维素钠置于研磨中，加入甘油研匀，然后边研匀边加入溶有苯甲酸钠和盐酸小檗碱的水溶液，待溶胀后研匀，即得。
使用方法：均匀涂抹患处，一日2次。
1、药效实验：镇痛作用
本部分实验对本发明的药物进行药效学研究。通过小鼠热刺激试验、小鼠醋酸扭体试验、小鼠甲醛致痛试验，观察小檗碱的镇痛作用。
1.1、实验材料和方法
1.1.1、小鼠热刺激致痛试验
昆明种雌性小鼠65只，体重18-22g，选取基础痛阈在5-30s之间的合格雌性小鼠，随机分成5组：空白对照组，扶他林阳性对照组，小檗碱高浓度组(10mg/ml)、中浓度组(5mg/ml)、低浓度组(2.5mg/ml)，每组13只。小鼠被放到预先加热至55℃左右的金属板上，以舔后足作为疼痛反映指标，观察给药前、后痛阈值的变化。每天给予相应的药物涂抹双足，连续给药5天，末次给药后测定0.5h、1h、1.5h、2h的小鼠痛阈值。
1.1.2、小鼠醋酸扭体试验
昆明种小鼠70只，体重18-22g，随机分成5组：空白对照组，扶他林阳性对照组，小檗碱高浓度组(10mg/ml)、中浓度组(5mg/ml)、低浓度组(2.5mg/ml)，每组15只。每天给予相应的药物涂抹腹部，连续给药5天，末次给药60min后，各组小鼠均腹腔注射0.7％醋酸0.1ml/10g，观察15min内小鼠的扭体反应次数。
1.1.3、小鼠甲醛致痛试验
昆明种小鼠70只，雌雄各半，体重18-22g，随机分为5组，分别为空白对照组、扶他林阳性对照组、小檗碱高浓度组(10mg/ml)、中浓度组(5mg/ml)、 低浓度组(2.5mg/ml)，每组14只，连续给药5天，末次给药后60min各组动物以微量注射器在左后足底皮下注射2.5％甲醛溶液(50ul/只)后立即置入平底大玻璃容器内，观察小鼠舔后足的累计时间(观察时间为注射后0-10min和15-30min两个时间段)。
1.2、实验结果
1.2.1、小檗碱对热刺激致痛的影响
实验结果表明，扶他林给药组在给药后0.5h、1.5h与空白对照组比较有明显差异(P＜0.05)，但小檗碱高、中、低剂量对热刺激引起的疼痛没有明显的镇痛作用。见表1。
表1、小檗碱对热刺激引起疼痛的影响(
n＝13)
注：与空白对照组比较，*P＜0.05，**P＜0.01。
1.2.2、小檗碱对醋酸扭体反应的影响
实验结果表明，小檗碱高、中剂量对醋酸引起的疼痛有明显的镇痛作用，与空白对照组比较，差异有显著性(P＜0.05)。见表2。
表2、小檗碱对醋酸诱发扭体反应的影响(
n＝14)
注：与空白对照组比较，*P＜0.05，**P＜0.01。
1.2.3、小檗碱对甲醛引发小鼠疼痛的影响
实验结果表明，小檗碱高、中剂量对甲醛引起的舔足反应在0-10min有明显的缓解作用，与空白对照比较，差异有显著性(P＜0.05)。见表3。
表3、小檗碱对甲醛诱发小鼠舔足反应的影响(
n＝12)
注：与空日对照组比较，*P＜0.05，**P＜0.01。
1.3、结论
小檗碱对小鼠热刺激致痛试验无明显镇痛作用，对甲醛、醋酸引起的疼痛有明显的镇痛作用。说明小檗碱具有一定的镇痛作用，对炎症引起的疼痛作用明显。
2、药效实验：抗炎作用
本部分实验对本发明的药物进行药效学研究。通过小鼠二甲苯耳肿胀试验、小鼠毛细血管通透性试验，观察小檗碱的抗炎作用。
2.1、实验材料和方法
2.1.1、小鼠二甲苯耳肿胀试验
小鼠随机分成5组：空白对照组，扶他林阳性对照组，小檗碱高浓度组(10mg/ml)、中浓度组(5mg/ml)、低浓度组(2.5mg/ml)，每组15只。连续给药7天，末次给药60min后，在小鼠左耳廓两面均匀涂抹二甲苯，右耳不涂为正常耳，30min后将小鼠脱颈椎处死，沿耳廓边缘剪下左、右两耳，用直径为6mm的打孔器在左右两侧耳相同部位取下圆耳片，立即用分析天平称重，计算耳廓肿胀度，并计算耳肿胀抑制率。
2.1.2、小鼠毛细血管通透性试验
小鼠60只，雌雄各半，体重18-22g，随机分为5组，空白对照组，阳性对照组，小檗碱高浓度组(10mg/ml)、中浓度组(5mg/ml)、低浓度组(2.5mg/ml)，每组12只。上述各组小鼠连续给药7天，第7天给药后60min，小鼠尾静脉注射0.5％伊文思蓝(0.1ml/10g)，随后立即腹腔注射0.6％醋酸(0.1ml/10g)，20min后脱臼处死，每只小鼠腹腔用6ml生理盐水冲洗，吸取腹腔液，3000rpm离心15min，取上清液于紫外分光光度计上590nm测定0D值。
2.2、实验结果
2.2.1、小檗碱对二甲苯小鼠耳肿胀的影响
实验结果表明，与空白对照比较，小檗碱高、中、低剂量对二甲苯引起的耳肿胀有显著的抑制作用(P＜0.01)，提示小檗碱对炎性渗出肿胀有显著的抑制作用。见表4。
表4、小檗碱对二甲苯耳肿胀的影响(
n＝15)
注：与空白对照组比较，*P＜0.05，**P＜0.01。
2.2.2、小檗碱对醋酸诱发小鼠毛细血管通透性增加的影响
实验结果表明，小檗碱高剂量组对醋酸引起的毛细血管通透性增加有明显的抑制作用，与空白对照比较，差异有显著性(P＜0.05)。见表5。
表5、小檗碱对小鼠毛细血管通透性的影响(
n＝15)
注：与空白对照组比较，*P＜0.05，**P＜0.01。
2.3、结论
小檗碱对二甲苯引起的耳肿胀及醋酸引起的毛细血管通透性增加有显著的抑制作用，说明小檗碱具有抗炎作用。
3、临床疗效观察：治疗急性软组织损伤
本部分实验对本发明的药物进行临床疗效观察。通过急性软组织损伤症状、体征及实验室检查，观察比较小檗碱的治疗效果。
3.1、临床资料与方法
选取符合急性软组织损伤诊断的临床病例200例。其中，男性105例，女性95例；年龄最大60岁，最小15岁；损伤部位为躯干或四肢。随机分为2组，一组采用扶他林治疗，作为对照组；另一组选用小檗碱制剂治疗，作为试验组。观察比较对照组和试验组的治疗效果。
3.2结果
实验结果表明，小檗碱治疗急性软组织损伤效果优于扶他林，总有效率为97％，结果见表6。与扶他林相比，小檗碱可有效减轻患者的肿胀和创面，周径差较小(P＜0.05)，瘀斑消减迅速(P＜0.01)，见表7。
表6、两组疗效的比较
表7、两组常见的急性软组织损伤症状、体征及实验室检查比较(
，n＝100)
注：与对照组比较，*P＜0.05，**P＜0.01；同组内与治疗前比较，#P＜0.05，##P＜0.01。
3.3结论
小檗碱可用于治疗急性软组织损伤。相比扶他林，小檗碱起效快、疗效好，更具临床优势。
综上所述，本发明的小檗碱具有良好的抗炎消肿作用，可以有效的减少急性软组织损伤患者的炎症渗出液，缓解疼痛症状。
本发明的小檗碱具有抗微生物、抗心律失常、降血脂、降血糖、抗炎、抗肿瘤、镇静催眠等多种药理作用。小檗碱经皮肤给药浓度高，直达病所，除了起局部作用外，还可通过皮肤进人血液循环，发挥全身作用，有效缓解患者的疼痛、肿胀症状。另外，皮肤角质层还有贮存作用，使血药浓度曲线平稳，有超越一般给药方法独特的优点。通过小鼠热刺激试验、小鼠醋酸扭体试验、小鼠甲醛致痛试验、小鼠二甲苯耳肿胀试验、小鼠毛细血管通透性试验证明中药单体成分小檗碱具有抗炎、镇痛功效，通过临床实例证明具有治疗急性软组织 损伤的作用。本发明为治疗急性软组织损伤提供一种中药单体成分新药，其功能明确、无毒副作用，拓宽了小檗碱防治疾病的范围，市场前景可观。
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改，并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此，本发明不限于上述实施例，本领域技术人员根据本发明的揭示，不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (5)
- 小檗碱在制备治疗急性软组织损伤的药物中的应用。
- 根据权利要求1所述的小檗碱在制备治疗急性软组织损伤的药物中的应用，其特征在于，按重量百分数计算，所述的药物中小檗碱的含量为1％～99.5％，其余为药学上可以接受的辅料。
- 根据权利要求1所述的小檗碱在制备治疗急性软组织损伤的药物中的应用，其特征在于，所述的药物是常规制药设备可以制得的剂型。
- 根据权利要求3所述的小檗碱在制备治疗急性软组织损伤的药物中的应用，其特征在于，所述的剂型为洗剂、喷雾剂、软膏剂和凝胶剂。
- 根据权利要求1所述的小檗碱在制备治疗急性软组织损伤的药物中的应用，其特征在于，按重量百分数计算，所述的药物中小檗碱的含量为99.5％。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710134599.1A CN106727542A (zh) | 2017-03-08 | 2017-03-08 | 小檗碱在制备治疗急性软组织损伤的药物中的应用 |
| CN201710134599.1 | 2017-03-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2018161890A1 true WO2018161890A1 (zh) | 2018-09-13 |
Family
ID=58961006
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2018/078132 WO2018161890A1 (zh) | 2017-03-08 | 2018-03-06 | 小檗碱在制备治疗急性软组织损伤的药物中的应用 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN106727542A (zh) |
| WO (1) | WO2018161890A1 (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106727542A (zh) * | 2017-03-08 | 2017-05-31 | 佛山市中医院 | 小檗碱在制备治疗急性软组织损伤的药物中的应用 |
| CN113171364A (zh) * | 2020-11-09 | 2021-07-27 | 厦门市健康医疗大数据中心(厦门市医药研究所) | 非口服小檗碱的用途 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120232031A1 (en) * | 2009-10-19 | 2012-09-13 | Panmira Pharmaceuticals, Llc | Injectable formulations for intra-articular or peri-articular administration |
| CN106727542A (zh) * | 2017-03-08 | 2017-05-31 | 佛山市中医院 | 小檗碱在制备治疗急性软组织损伤的药物中的应用 |
| CN106902114A (zh) * | 2017-03-08 | 2017-06-30 | 佛山市中医院 | 一种治疗急性软组织损伤的药物组合物 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140186306A1 (en) * | 2012-09-28 | 2014-07-03 | Paul Ronald Plante | Novel ampk agonist compositions and methods of use |
-
2017
- 2017-03-08 CN CN201710134599.1A patent/CN106727542A/zh active Pending
-
2018
- 2018-03-06 WO PCT/CN2018/078132 patent/WO2018161890A1/zh active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120232031A1 (en) * | 2009-10-19 | 2012-09-13 | Panmira Pharmaceuticals, Llc | Injectable formulations for intra-articular or peri-articular administration |
| CN106727542A (zh) * | 2017-03-08 | 2017-05-31 | 佛山市中医院 | 小檗碱在制备治疗急性软组织损伤的药物中的应用 |
| CN106902114A (zh) * | 2017-03-08 | 2017-06-30 | 佛山市中医院 | 一种治疗急性软组织损伤的药物组合物 |
Non-Patent Citations (2)
| Title |
|---|
| LIN, JIAOYU: "Comparative transdermal Penetration study on Berberine Hydrochloride accelerated by Aloin and commonly absorption promoter", MEDICINE & PUBLIC HEALTH, vol. S1, 15 December 2011 (2011-12-15), pages 6, 34 * |
| LIU, XIAOLEI: "Experiment Research the Penetration Amount of Berberine Hydrochloride in treats by ultrasonic transdermal drug delivery", SOCIAL SCIENCE (B), vol. 1, 15 January 2014 (2014-01-15), pages 1, 4 - 8, 10 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106727542A (zh) | 2017-05-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105142728B (zh) | 用于治疗表面创伤的组合物和方法 | |
| WO2017206758A1 (zh) | 皮肤多种损伤创面治疗的外用药物组合物及其制备方法 | |
| CN102258746B (zh) | 烧烫伤创面处理软膏 | |
| WO2006076844A1 (fr) | Medicament chinois traditionnel destine a traiter les blessures resultant de chutes, rhumatisme et ostealgie et son procede de fabrication | |
| WO2001056583A1 (fr) | Medicament contenant une anemonine efficace pour traiter les inflammations aseptiques | |
| EA029649B1 (ru) | Гель на основе полифенолов гранатовой кожуры для лечения воспалительных заболеваний в гинекологии и способ его приготовления | |
| CN104983891B (zh) | 用于治疗伤口的中药组合物及基于该中药组合物的中药油敷料的制备方法 | |
| WO2014118040A1 (en) | Extract from indigo tinctoria for the topical treatment and prophylaxis of skin disorders | |
| CN101703651B (zh) | 一种治疗糖尿病坏疽的药物 | |
| CN101829130A (zh) | 复方白藜芦醇抗炎止痒药物组合及用途 | |
| WO2018161890A1 (zh) | 小檗碱在制备治疗急性软组织损伤的药物中的应用 | |
| WO2012100754A1 (zh) | 一种治疗刀伤、烧伤及多种创伤中药组合物 | |
| CN102228554B (zh) | 一种治疗烧伤烫伤的药物及其制备方法 | |
| CN115381912B (zh) | 一种降低癌性疼痛的外用中药复方制剂及其制备方法 | |
| CN106822321B (zh) | 伤科黄水在制备治疗毛周角化症的药物中的应用 | |
| CN104815068A (zh) | 一种头孢氨苄软膏及制备方法 | |
| US10980762B2 (en) | Wound healing composition | |
| CN103263451B (zh) | 一种主治外伤、疮疡的中药及其制备方法和应用 | |
| CN107468815A (zh) | 一种速效止痛的外用中药组合物 | |
| CN113813308A (zh) | 一种治疗烧烫伤的药物及其制备方法 | |
| TW201309317A (zh) | 一種用於治療傷口癒合的植物萃取物 | |
| CN108635362B (zh) | 一种治疗糖尿病足的药物组合物 | |
| CN111388523A (zh) | 一种治疗痤疮的制剂及其制备方法 | |
| CN101361938A (zh) | 含天然珊瑚姜油的冻疮膏 | |
| CN100355437C (zh) | 一种治疗烧烫伤的药物及其制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18764336 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 18764336 Country of ref document: EP Kind code of ref document: A1 |
|
| 32PN | Ep: public notification in the ep bulletin as address of the adressee cannot be established |
Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 06.03.2020) |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 18764336 Country of ref document: EP Kind code of ref document: A1 |