CN113855626B - Capsaicin injection for treating osteoarthritis and preparation method thereof - Google Patents
Capsaicin injection for treating osteoarthritis and preparation method thereof Download PDFInfo
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- CN113855626B CN113855626B CN202010788134.XA CN202010788134A CN113855626B CN 113855626 B CN113855626 B CN 113855626B CN 202010788134 A CN202010788134 A CN 202010788134A CN 113855626 B CN113855626 B CN 113855626B
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Classifications
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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Abstract
The invention discloses a capsaicin injection for treating osteoarthritis and a preparation method thereof, the capsaicin injection consists of capsaicin, an organic solvent, a pH regulator and water, and the content of the organic solvent is 40-80% (w/w).
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and relates to a capsaicin injection for treating osteoarthritis and a preparation method thereof.
Background
OA (Osteoarthritis) Osteoarthritis is a degenerative disease, which is caused by degenerative damage of articular cartilage, reactive hyperplasia of articular margin and subchondral bone, and is also called osteoarthropathy, degenerative arthritis, senile arthritis, hypertrophic arthritis, etc. due to various factors such as aging, obesity, strain, trauma, congenital abnormality of joints, joint deformity, etc. The clinical manifestations are slowly developing joint pain, tenderness, stiffness, joint swelling, limited mobility and joint deformity. Is the eighth most common disease in subjects between 65-74 years of age for primary care physician treatment, while it is the third most common disease in subjects over 75 years of age (Mamlin et al, 1998. U.S. DHHS, 1992). Knee osteoarthritis is characterized by chronic pain, cartilage matrix degradation, loss of synovial fluid, osteophyte formation and episodic inflammation (Caborn et al, 2004). Knee replacement or positive non-surgical intervention can address the debilitating effects of end-of-knee OA. Subjects with OA may thus be distressed, often interfering with the ability of the patient to perform daily tasks such as walking or climbing stairs. The main symptom is joint pain, which often occurs in morning, but the pain is relieved after activity, but the pain may be aggravated if the activity is too much. Another symptom is joint stiffness, which often occurs when the joint gets up in the morning or after the joint remains in a certain position for a long time during the day. The affected joints are examined to be swollen and painful, and have friction or "clicking" sound during movement, while those with severe disease may have muscular atrophy and joint deformity.
The main treatment method of the disease is to reduce the load and excessive large-amplitude movement of the joints so as to delay the progress of the disease. Obese patients should lose weight and reduce the load on the joints. When the joints of the lower limbs have pathological changes, a crutch or a walking stick can be used to reduce the burden of the joints. Physical therapy and proper exercise can keep the range of motion of joints, and splint supports, walking sticks and the like can be used as necessary, thereby being helpful for controlling acute symptoms. Anti-inflammatory analgesic drugs can alleviate or control symptoms, but should be used with caution and not taken for a long time after assessing patient risk factors. Chondroprotective agents such as glucosamine sulfate have symptomatic relief and improved function, while long-term administration can delay the structural progression of the disease. For the later stage of cases, the artificial joint replacement is a recognized effective method for eliminating pain, correcting deformity and improving functions under the condition that the general condition can tolerate the operation, and the life quality of patients can be greatly improved. In general, there is currently a lack of effective, reversible medications for osteoarthritis. The guidelines for osteoarthritis diagnosis and treatment, which were developed by the college of medicine rheumatology division in 2010 (reference: college of medicine rheumatology division, arthritis diagnosis and treatment guideline [ J ]. The college of rheumatism science 2010, 6 th 14 th volume: 416-419), indicate that OA medication is mainly divided into a medicine for controlling symptoms, a medicine for improving disease conditions and a chondroprotective agent. The clinically commonly used drugs include: (1) non-steroidal anti-inflammatory drugs (NSAIDS): such as ibuprofen, celecoxib, and sertraline, which may be administered orally or topically, often as a first line drug for the treatment of osteoarthritis. However, NSAIDS have the side effects of gastrointestinal mucosal damage, especially in patients with peptic ulcers.
(2) Glucocorticoids: the injection is usually used by local injection, has obvious effects of improving inflammation and relieving pain, but should be limited to use, and can cause damage to joints after repeated use.
(3) Opioid drugs: such as oxycodone and Qimanting, can be orally or externally used, mainly aims at more than moderate chronic pain, and has the main side effects of dizziness and vomiting.
(4) Joint cavity injection medicine: such as sodium hyaluronate, which acts to lubricate joints.
(5) The glucosamine preparation has unknown action mechanism, and the medicine has the effects of reducing the activities of matrix protease, collagenase and the like, resisting inflammation, relieving pain, protecting articular cartilage and delaying the development of OA. The existing medicine generally has slow effect, needs to be treated for a plurality of weeks to take effect, and is mainly used as slow acting medicine for osteoarthritis.
Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a pungent component in capsicum, one of the oldest cultivated plants in america (Perry et al, 2007. Lotions (0.025% and 0.075% w/w) are widely used as over the counter treatments to treat pain due to neuralgia, arthritis, soreness of the waist, muscle soreness and other conditions. In addition, in 2009, the FDA approved quatenza, a transdermal patch made of 8% capsaicin, for the treatment of neuropathic pain associated with post-herpetic neuralgia (PHN).
Capsaicin causes a transient, intense sensation of pain after injection into the skin. This is followed by analgesia caused by the inactivation of the TRPV 1-expressing nociceptors. Prolonged inactivation has been the focus of many therapeutic applications of capsaicin, including the treatment of pain. Inactivation is accompanied by degeneration of nociceptor fibers, which then regenerate over a period of weeks to months (Simone et al, 1998. Rapid inactivation specific to nociceptors provides the opportunity to improve pain for weeks to months with a single injection. Non-clinical and clinical studies with capsaicin have demonstrated that capsaicin is an effective, long-lasting analgesic after a single topical application, and has a short systemic drug exposure time (minimizing systemic side effects). The side effects and safety to date are similar to those of placebo. Other investigational uses for capsaicin include pain relief in subjects with Human Immunodeficiency Virus (HIV) -associated sensory neuropathy, treatment of bladder hyperreflexia, chronic neck pain, infusion site pain, diabetic neuropathy, osteoarthritis, labor pain, pain after tooth extraction from a molar and pain caused by nerve injury.
Capsaicin (CAP) is a poorly soluble drug and is soluble in ethanol, and currently, preparations sold at home and abroad mainly comprise gel patches and creams. In the prior art, the literature reports that direct application of capsaicin can delay wound healing and produce burning pain on skin, which may be related to local microenvironment change at the wound part and strong irritation of capsaicin, and the external preparation needs to be used for several days to be tolerated by patients. Because CAP has physical and chemical characteristics, the clinical application is limited, and the invention improves the solubility of the capsaicin by solubilization on the basis of the mechanism, can prepare a capsaicin solution with good stability for injection, and can realize quick-acting and long-acting OA symptom relieving effect.
Although the existing capsaicin patch has the functions of relieving pain and diminishing inflammation, the problem of skin irritation (burning sensation and stabbing pain sensation generated at the application position) needs to be improved, and the capsaicin patch can be only used for intact skin and not used for skin injury positions.
At present, aiming at the field of OA treatment, a quick-acting and long-acting treatment medicine with definite pertinence is not available temporarily, the OA treatment is limited to short-term use, and long-acting effect cannot be realized, so that the product can provide a new idea for the OA treatment.
Patent document cn201780075307.X discloses a stable aqueous capsaicin injectable preparation and medical application thereof, the document uses long-chain fatty acid polyglycol ester as a solubilizer, a low pH is required for ensuring the dissolution state of the solubilizer, the prepared preparation causes irritation in clinical application due to low pH, the document indicates that the injection needs to be used together with an anesthetic and cannot be used alone when in use, and the safety of the long-chain fatty acid polyglycol ester in the application of a water needle injection needs to be confirmed.
Patent document CN200380109828.0 discloses a composition and method for alleviating pain in a part of a human or animal in need thereof by administering a capsaicinoid to said part, which provides the idea of using a capsaicin preparation for treating pain, the basic formulation of which is capsaicin and a carrier, which can be prepared into different dosage forms for different administration routes for different indications, but the document does not describe specific technical contents.
Disclosure of Invention
The invention aims to provide a capsaicin injection with simple preparation method, small toxic and side effects, quick curative effect and long acting, and the invention specifically comprises the following steps:
the invention provides a capsaicin injection, which consists of capsaicin, an organic solvent, a pH regulator and water, wherein the content of the organic solvent is 40-80% (w/w), and preferably 40-60% (w/w). As an illustrative illustration, the amount of organic solvent may be 40%, 45%, 50%, 55%, 60%,65%, 70%, 75%, or 80%.
In the present invention, as one embodiment, the organic solvent is selected from ethanol, propylene glycol, butylene glycol, PEG-200, PEG-300, PEG-400, PEG-500, or PEG-600, or a combination of two or more thereof, preferably PEG-200 and/or PEG-300.
In the present invention, as one of the embodiments, the pH adjusting agent adjusts the pH of the injection to 4 to 9, preferably 6 to 8, and the optimum pH is 6.5 to 7.5.
In the present invention, as one embodiment, the pH adjuster is an alkaline or acidic adjuster.
In the present invention, as one embodiment, the alkaline pH adjuster is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, diethanolamine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, tris (Tris), arginine, lysine, histidine, or glycine, or a combination of two or more thereof, preferably sodium hydroxide.
In one embodiment of the present invention, the acidic pH adjusting agent is selected from ascorbic acid, lactic acid, malic acid, fumaric acid, citric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid, or acetic acid, or a combination of two or more thereof, preferably citric acid.
In the present invention, as one embodiment, the pH adjuster is alkaline sodium hydroxide and acidic citric acid.
In the present invention, as one embodiment, the content of capsaicin in the injection is 0.01% to 0.5% (w/w), preferably 0.02% to 0.3% (w/w), and most preferably 0.05% to 0.2% (w/w).
In the present invention, as one embodiment, the injection formulation comprises: the ratio of water is 40.
In the present invention, as one embodiment, the water is water for injection.
In the present invention, as one embodiment, the injection is prepared from
Or is made of
Or is made of
Or is made of
In the present invention, as one embodiment, the injection can be optionally used after being combined with 0.9% physiological saline or 5% glucose solution.
As an illustrative example, a corresponding volume of 0.9% saline or 5% glucose solution may be prepared in a compatible volume ratio of 1 to 1.
In the present invention, as one embodiment, the injection after the formulation is administered by local injection.
In the present invention, as one embodiment, the injection after formulation is used by injecting into the joint cavity.
The present invention also provides a method for preparing the aforementioned capsaicin injection, comprising:
(a) Mixing capsaicin with an organic solvent, dissolving, stirring until the mixture is clear, adding water for injection, and stirring and mixing uniformly to obtain a solution 1;
(b) Adding a pH regulator into the solution 1 to obtain a solution 2;
(c) Filtering the solution 2 through a microporous filter membrane, and filling;
(d) Filling the liquid medicine and sterilizing.
In the present invention, as one embodiment, the stirring time of the capsaicin and the organic solvent in the step (a) is 5 to 10 minutes or more, and may be 20 minutes, 30 minutes, 40 minutes, 50 minutes or more until the drug powder is completely dissolved.
In the present invention, as one embodiment, the microporous filter membrane in the step (c) is a PES or PVDF filter membrane of 0.45 μm, 0.65 μm, 0.80 μm, preferably a PES filter membrane of 0.45 μm.
In the present invention, as one embodiment, the sterilization mode in the step (d) is 115 ℃ to 121 ℃ and sterilization is performed for 8 to 45min; preferably sterilizing at 115 deg.C for 30-45min or 121 deg.C for 8-30min; further preferably sterilizing at 121 deg.C for 8-15 min, preferably at 121 deg.C for 8min.
In the present invention, as one embodiment, the sterilization in the step (d) is performed by filtration sterilization through a 0.22 μm filter.
In the present invention, as one embodiment, the filling volume in the step (d) is 0.5 to 5ml, preferably 1 to 3ml, and most preferably 1 to 2ml.
In one embodiment of the present invention, the final concentration of the drug solution is 0.01% to 0.5% (w/w), preferably 0.02% to 0.3% (w/w), and most preferably 0.05% to 0.2% (w/w).
In the present invention, as one embodiment, the method further comprises:
adding CAP into PEG-300 under stirring, stirring at room temperature to dissolve it to be clear, adding water for injection, stirring at room temperature, and adjusting pH of the liquid medicine with pH regulator to obtain the final product; filtering with 0.45 μm microporous membrane, filtering with 0.22 μm membrane for sterilization, and sealing with a pressure cover; or filtering with 0.45 μm microporous membrane, packaging in ampoule, and sterilizing at 121 deg.C for 8min.
In the present invention, as one embodiment, the injection formulation comprises: the mass ratio of water is 40.
The invention provides a clear and transparent solution prepared by mixing and stirring capsaicin and a proper solvent, and the solution for injection is obtained after indexes such as compatibility dilution, osmotic pressure regulation, pH regulation and the like. The preparation method comprises the following steps:
(a) Mixing capsaicin with a proper organic solvent, dissolving, stirring until the mixture is clear, adding water for injection, and stirring and mixing uniformly to obtain a solution 1;
(b) Adding a proper pH regulator into the solution 1 to obtain a solution 2;
(c) Filtering the solution 2 through a proper microporous filter membrane, and filling;
(d) Filling the liquid medicine for sterilization; wherein the solvent in (a) may be one, two or more of ethanol, propylene glycol, butanediol, polyethylene glycol (PEG-200, PEG-300, PEG-400, PEG-500, PEG-600), etc., preferably PEG-200 and/or PEG-300;
in the present invention, as one of the embodiments, the ratio of the capsaicin-solvent composition to the water for injection in step (a) may be 40;
in the present invention, as one embodiment, the stirring time of the capsaicin with the suitable organic solvent in the step (a) may be 5 to 10 minutes or more, and may be 20 minutes, 30 minutes, 40 minutes, 50 minutes or more until the drug powder is completely dissolved;
in the present invention, as one of the embodiments, the pH adjusting agent in the step (b) may be an alkaline or acidic adjusting agent, and the alkaline pH adjusting agent may be one, two or more selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, diethanolamine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, tris (Tris-hydroxymethyl aminomethane), arginine, lysine, histidine and glycine; the acidic pH regulator may be one, two or more of ascorbic acid, lactic acid, malic acid, fumaric acid, citric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid and acetic acid, preferably alkaline sodium hydroxide and/or acidic citric acid;
in the present invention, as one of the embodiments, the pH in the step (b) may be adjusted to 4 to 9, preferably 6 to 8;
in the present invention, as one embodiment, the microporous membrane in step (c) may be PES or PVDF membrane of 0.45 μm, 0.65 μm or 0.80 μm, preferably PES membrane of 0.45 μm;
in the present invention, as one embodiment, the sterilization mode in the step (d) may be 45min at 115 ℃, 30min at 115 ℃,8min at 121 ℃, 15min at 121 ℃, or 30min at 121 ℃, preferably 8-15 min at 121 ℃;
in the present invention, as one embodiment, the filling volume in the step (d) may be 1ml, 2ml, 3ml, 5ml.
The final concentration of the resulting solution may be 0.5mg/ml, 1mg/ml, 2mg/ml, 4mg/ml, or 5mg/ml.
The invention has the following advantages:
(1) The existing administration route and administration mode of the CAP preparation are changed, and the problem of skin irritation is avoided;
(2) Provides a new treatment idea for the field of OA treatment;
(3) The preparation provided by the invention has the advantages of simple preparation mode, small toxic and side effects, and quick and long-acting curative effect.
The invention changes the existing drug administration mode and drug administration route of the CAP drug in the market, avoids the skin irritation problem of the existing external preparation, better utilizes the analgesic mechanism of the CAP, applies the CAP drug to the field of OA treatment, provides a new idea for the OA treatment and further exerts the drug effect of the CAP.
The invention screens out proper solubilizer by screening the types and the dosage of the solvents, improves the problem of poor solubility of the capsaicin, can prepare the capsaicin solution for injection on the premise of ensuring the safety and reducing the irritation, provides definite prescription composition, has simple prescription composition, selects the auxiliary materials which are all common injection components with good safety, and performs the stability inspection of the preparation, and the inspection result shows that the preparation of the prescription has good stability. The injection is administrated by single-dose local injection, such as joint cavity injection, and has quick-acting and long-acting remarkable effect on OA treatment.
The preparation of the invention has simple preparation process and obvious pharmacological action.
Detailed Description
The following examples and experimental examples are intended to further illustrate the present invention, but are not intended to limit the effective scope of the present invention in any way.
Example 1:
1) Prescription composition
| Components | Prescription amount (g) |
| CAP | 0.2 |
| PEG-200 | 100 |
| Water for injection | 100 |
| Citric acid/sodium hydroxide | Adjusting pH to 6.2 |
The preparation method comprises the following steps: adding CAP in the amount of the prescription into PEG-200 under stirring, stirring at room temperature to dissolve the CAP until the CAP is clear, adding water for injection, stirring at room temperature, and adjusting the pH value of the liquid medicine to 6.2 with a pH regulator. No precipitation or other insoluble particles/visible foreign matter appeared upon standing at room temperature.
Example 2:
1) Prescription composition
The preparation method comprises the following steps: adding CAP in the amount of the prescription into PEG-300 under stirring, stirring at room temperature to dissolve the CAP until the CAP is clear, adding water for injection, stirring uniformly at room temperature, and adjusting the pH value of the liquid medicine to 7.4 by using a pH regulator to obtain the final product. No precipitation or other insoluble particles/visible foreign matter appeared upon standing at room temperature. Filtering with 0.45 μm microporous membrane, placing 5mL into 10mL penicillin bottle, sealing with pressure cap, and respectively placing the preparation under different conditions such as influencing factors (high temperature, illumination), accelerating condition, and long-term condition for stability investigation.
Example 3:
1) Prescription composition
| Components | Prescription amount (g) |
| CAP | 0.4 |
| PEG-400 | 100 |
| Water for injection | 100 |
| Citric acid/sodium hydroxide | Adjusting pH to 6.9 |
The preparation method comprises the following steps: adding CAP in the amount of the prescription into PEG-400 under stirring, stirring at room temperature to dissolve the CAP until the CAP is clear, adding water for injection, stirring uniformly at room temperature, and adjusting the pH value of the liquid medicine to 6.9 by using a pH regulator to obtain the final product. No precipitation or other insoluble particles/visible foreign matter appeared upon standing at room temperature.
Example 4:
1) Prescription composition
The preparation method comprises the following steps: the procedure was as in example 2.
Example 5:
1) Prescription composition
| Components | Prescription amount (g) |
| CAP | 0.125 |
| PEG-300 | 100 |
| Water for injection | 150 |
| Citric acid/sodium hydroxide | Adjusting pH to 7.4 |
The preparation method comprises the following steps: the procedure was as in example 2.
Example 6:
1) Prescription composition
| Components | Prescription dose (g) |
| CAP | 0.25 |
| PEG-300 | 150 |
| Water for injection | 100 |
| Citric acid/sodium hydroxide | Adjusting pH to 7.4 |
The preparation method comprises the following steps: the procedure was as in example 2.
Example 7: solubility investigation
Preparing solutions with different pH values and different solvents by referring to a preparation method of buffer solution of four general rules of Chinese pharmacopoeia 2015 edition: phosphate buffer at pH 5.8, phosphate buffer at pH 6.5, phosphate buffer at pH 7.4, phosphate buffer at pH 8.0, 0.1M sodium hydroxide solution, 1M sodium hydroxide solution, 0.1M hydrochloric acid solution, 1M hydrochloric acid solution, and polyethylene glycol (PEG 200, PEG 300). 10mg of the drug substance was dissolved in 10ml of a solvent, and the dissolution was visually observed to determine the appearance and properties and to determine the appropriate dissolution conditions (solvent/diluent).
From the above results, it was found that CAP was insoluble in phosphate buffers of various pH values, in hydrochloric acid solution, in sodium hydroxide solution, and in PEG solutions of different molecular weights. In view of the safety and irritation of injections, PEG having higher safety and less irritation is preferably used as a solvent.
Example 8:
investigation of different solvent ratios (PEG: purified water) of liquid medicine
Based on the prescription process of example 2, liquid medicines with different solvent ratios and the theoretical concentration of the medicine content of 1mg/g are prepared, the dissolution phenomenon of the raw material medicine is observed visually, and the proper solvent ratio is investigated and screened.
The investigation result shows that the clarity of the liquid medicine is reduced along with the reduction of the organic solvent ratio, the organic phase ratio is required to be more than 40% (w/w) in order to ensure the good clarity of the liquid medicine and the good dissolution state of the medicine, the dosage of the organic phase is limited in consideration of the safety of the injection formulation, and the organic phase ratio is preferably 40-60% (w/w) in combination with the maximum dosage range of the FDA inactive component IIG.
PEG is formed by gradually adding and polymerizing ethylene oxide and water or ethylene glycol, is liquid at normal temperature when the molecular weight is 200-600, contains a large number of hydroxyl groups in the structure, so that the polymer has stronger solubilization property, PEG200, PEG400, PEG500 and PEG600 which are liquid in the physical state have similar solubilization capacity, and through research, PEG with different types in a limited range accords with the proportion rule.
Comparative example 1:
1) Prescription composition
| Components | Amount of prescription |
| CAP | 0.1 |
| PEG-600 | 49.9 |
| Water for injection | 100 |
| Lactic acid/sodium hydroxide | Proper amount of |
The preparation method comprises the following steps: adding CAP of a prescription amount into PEG-600 under stirring, stirring at room temperature to dissolve the CAP until the CAP is clear, adding water for injection, stirring at room temperature, adding appropriate amount of sodium chloride for injection, and adjusting pH of the liquid medicine to 8.6 with pH regulator. No precipitation or other insoluble particles/visible foreign matter appeared upon standing at room temperature. The medicine has long dissolving time, and the liquid medicine is milky viscous liquid.
Comparative example 2:
1) Prescription composition
| Components | Amount of prescription |
| CAP | 0.5 |
| PEG-300 | 15 |
| Water for injection | 35 |
| Citric acid/sodium hydroxide | Proper amount of |
The preparation method comprises the following steps: adding CAP of a prescription amount into PEG-300 under stirring, stirring at room temperature to dissolve the CAP until the CAP is clear, adding water for injection, stirring uniformly at room temperature, adding a proper amount of sodium chloride for injection, and adjusting the pH value of the liquid medicine to 7.9 by using a pH regulator to obtain the CAP. No precipitation or other insoluble particles/visible foreign matter appeared upon standing at room temperature. The medicine has long dissolving time and low clarity of the liquid medicine.
Comparative example 3:
1) Prescription composition
| Components | Amount of prescription |
| CAP | 0.5 |
| PEG-300 | 99.8 |
| Water for injection | 100 |
| Citric acid/sodium hydroxide | Proper amount of |
The preparation method comprises the following steps: uniformly mixing PEG300 and water for injection according to the prescription amount, adding CAP of the prescription amount into a PEG 300-water mixed solvent under stirring, stirring at room temperature to dissolve the CAP until the CAP is clear, adding a proper amount of sodium chloride for injection, and adjusting the pH value of the liquid medicine to 7.4 by using a pH regulator to obtain the PEG 300-water mixed solvent. No precipitation or other insoluble particles/visible foreign matter appeared upon standing at room temperature. The medicine dissolution time is long, and the clarity of the liquid medicine is slightly low.
Experimental example 1 investigation result of stability of formulation
The content of the main drug in the solution is determined by an HPLC method, the content percentage is calculated, the stability of the preparation is evaluated by the content change, and the results are shown in the following table.
Table 1 example 2 results of stability study of sample formulations
The product has reduced content under illumination, and shows instability tendency, which indicates that the preparation should be protected from light during production, storage, transportation, etc. The stability under high temperature and other stability conditions is good, and the content and appearance indexes are not obviously changed after the accelerated condition is examined for 6 months and the long-term condition is examined for 12 months.
TABLE 2
For the preferred proportions of organic solvent: purified water =40, sample prepared from 60-60, with the degree of content degradation within 5% when examined under accelerated (40 ℃) conditions for 6 months, within 3% when examined under intermediate (30 ℃) and long-term (25 ℃) conditions for 6 months, and with the rate of change below 5%, indicating good stability of the sample.
Claims (33)
1. A capsaicin injection is characterized in that the injection consists of capsaicin, an organic solvent, a pH regulator and water, the content of the organic solvent is 40-80% (w/w), wherein,
the organic solvent is selected from PEG-200, PEG-300, PEG-400, PEG-500, or PEG-600, or a combination of two or more of them, the organic solvent: the mass ratio of water is 40;
the content of the capsaicin in the injection is 0.01-0.5% (w/w);
the pH value of the injection is 4-9, and the pH regulator is alkaline sodium hydroxide or acidic citric acid.
2. The injection according to claim 1, wherein the organic solvent is selected from PEG-200 and/or PEG-300.
3. The injection according to claim 1, wherein the pH-adjusting agent adjusts the pH of the injection to 6-8.
4. The injection according to claim 1, wherein the capsaicin is present in an amount of 0.02-0.3% (w/w).
5. The injection according to claim 1, wherein the ratio of organic solvent: the mass ratio of water is 40.
6. The injection according to claim 1, wherein the water is water for injection.
7. The injection according to claim 1, wherein the injection is prepared from
Capsaicin 0.5g
PEG-300 100g
150g of water for injection
Citric acid/sodium hydroxide in proper amount to regulate pH to 7.4;
or is made of
Capsaicin 0.25g
PEG-300 150g
100g of water for injection
Citric acid/sodium hydroxide in proper amount to regulate pH to 7.4;
or is made of
Capsaicin 0.2g
PEG-200 100g
100g of water for injection
Citric acid/sodium hydroxide in proper amount to regulate pH to 6.2;
or is made of
Capsaicin 0.4g
PEG-400 100g
100g of water for injection
Citric acid/sodium hydroxide in appropriate amount to adjust pH to 6.9.
8. The injection according to claim 1, wherein the injection is used after being combined with 0.9% physiological saline or 5% glucose solution.
9. The injectable formulation of claim 8, wherein said formulated injectable formulation is administered by topical injection.
10. The injectable formulation of claim 9, wherein said formulated injectable formulation is administered by intra-articular injection.
11. A method for preparing the capsaicin injection according to claim 1, comprising:
(a) Mixing capsaicin with an organic solvent, dissolving, stirring until the mixture is clear, adding water for injection, and stirring and mixing uniformly to obtain a solution 1;
(b) Adding a pH regulator into the solution 1 to obtain a solution 2;
(c) Filtering the solution 2 through a microporous filter membrane, and filling;
(d) Filling the liquid medicine and sterilizing.
12. The method as claimed in claim 11, wherein the capsaicin and the organic solvent are stirred for 5-10 minutes or more in step (a) until the drug powder is completely dissolved.
13. The method as claimed in claim 11, wherein the microfiltration membrane in step (c) is a PES or PVDF membrane of 0.45 μm, 0.65 μm or 0.80 μm.
14. The method according to claim 11, wherein the sterilization mode in the step (d) is sterilization at 115 ℃ to 121 ℃ for 8 to 45min.
15. The method according to claim 11, wherein the sterilization in step (d) is performed by filtration sterilization through a 0.22 μm filter.
16. The method of claim 11, wherein the fill volume in step (d) is 0.5-5ml.
17. The method of claim 11, wherein the final concentration of the drug solution is 0.01% to 0.5% (w/w).
18. The method of claim 11, further comprising:
adding CAP into PEG-300 under stirring, stirring at room temperature to dissolve CAP to be clear, adding water for injection, stirring at room temperature, and adjusting pH of the medicinal liquid with pH regulator; filtering with 0.45 μm microporous membrane, filtering with 0.22 μm membrane for sterilization, and sealing with a pressure cover; or filtering with 0.45 μm microporous membrane, packaging in ampoule, and sterilizing at 121 deg.C for 8min.
19. The injection according to claim 1, wherein the content of the organic solvent is 40% to 60% (w/w).
20. The injection according to claim 1, wherein the pH-adjusting agent adjusts the pH of the injection to 6.5-7.5.
21. The injection according to claim 4, wherein the capsaicin is present in an amount of 0.05-0.2% (w/w).
22. The injection according to claim 1, wherein the ratio of organic solvent: the mass ratio of water is 40.
23. The method as set forth in claim 12, wherein the stirring time of the capsaicin with the organic solvent in the step (a) is 20 minutes, 30 minutes, 40 minutes, 50 minutes or more.
24. The method as claimed in claim 13, wherein the microfiltration membrane in step (c) is a 0.45 μm PES membrane.
25. The method of claim 14, wherein the sterilization in step (d) is performed at 115 ℃ for 30-45min or at 121 ℃ for 8-30min.
26. The method according to claim 14, wherein the sterilization mode in the step (d) is sterilization at 121 ℃ for 8-15 min.
27. The method according to claim 14, wherein the sterilization mode in the step (d) is sterilization at 121 ℃ for 8min.
28. The method of claim 16, wherein the fill volume in step (d) is 1-3ml.
29. The method of claim 16, wherein the fill volume in step (d) is 1-2ml.
30. The method as claimed in claim 17, wherein the capsaicin is present in an amount of 0.02% to 0.3% (w/w) in the injection.
31. The method as claimed in claim 17, wherein the capsaicin is present in an amount of 0.05-0.2% (w/w) in the injection.
32. The method of claim 11, wherein the ratio of organic solvent in the injection: the mass ratio of water is 40.
33. The method of claim 11, wherein the ratio of organic solvent in the injection: the mass ratio of water is 40.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103070851A (en) * | 2012-07-23 | 2013-05-01 | 中国人民解放军兰州军区乌鲁木齐总医院 | Compound capsaicin preparation and applications thereof |
| CN105960230A (en) * | 2013-11-12 | 2016-09-21 | Vizuri健康科学有限责任公司 | Aqueous based capsaicinoid formulations and methods of manufacture and use |
| CN110035740A (en) * | 2016-11-02 | 2019-07-19 | 中枢疗法公司 | Stable aqueous capsaicine injectable formulation and its medical usage |
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2020
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| CN103070851A (en) * | 2012-07-23 | 2013-05-01 | 中国人民解放军兰州军区乌鲁木齐总医院 | Compound capsaicin preparation and applications thereof |
| CN105960230A (en) * | 2013-11-12 | 2016-09-21 | Vizuri健康科学有限责任公司 | Aqueous based capsaicinoid formulations and methods of manufacture and use |
| CN110035740A (en) * | 2016-11-02 | 2019-07-19 | 中枢疗法公司 | Stable aqueous capsaicine injectable formulation and its medical usage |
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