CN114903851A - Capsaicin fat emulsion - Google Patents
Capsaicin fat emulsion Download PDFInfo
- Publication number
- CN114903851A CN114903851A CN202110180761.XA CN202110180761A CN114903851A CN 114903851 A CN114903851 A CN 114903851A CN 202110180761 A CN202110180761 A CN 202110180761A CN 114903851 A CN114903851 A CN 114903851A
- Authority
- CN
- China
- Prior art keywords
- capsaicin
- milk
- water
- parts
- injection
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 title claims abstract description 213
- 235000017663 capsaicin Nutrition 0.000 title claims abstract description 106
- 229960002504 capsaicin Drugs 0.000 title claims abstract description 106
- 239000002960 lipid emulsion Substances 0.000 title claims abstract description 34
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims abstract description 33
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Classifications
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- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
The invention provides a capsaicin fat emulsion and a preparation method thereof, the fat emulsion contains capsaicin, oil for injection and lecithin, but the solution does not contain organic solvent, the emulsion is uniform and clear, the preparation process is simple, the amplification is easy, the solubility and the stability of the capsaicin are effectively improved, the side effect can be reduced to a certain degree, and the fat emulsion can be used for local or systemic administration to treat various types of pain, and the application range is wide.
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 many 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, and the third most common disease in subjects over 75 years of age (Mamlin et al, 1998; 2003). DHHS, 1992, usa). 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. A subject with OA may thus be distressing and often interfere with the patient's ability to perform daily tasks such as walking or climbing stairs. The main symptom is joint pain, which often occurs in the morning, but the pain is relieved after activities, but if activities are excessive, the pain may be aggravated. Another symptom is stiff joints, which often appear when getting up in the morning or after the joints remain in a certain position for a long time during the day. When the affected joint is examined, the joint may swell, press pain, and feel fricative or "clicking" during movement, and the patient with serious disease may have muscular atrophy and joint deformity.
The main treatment method of the disease is to reduce the load and excessive and 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 the joints, and splint supports, walking sticks and the like can be used when 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. In the case of later stage, under the condition that the whole body can endure the operation, the artificial joint replacement is the accepted effective method for eliminating pain, correcting deformity and improving functions, and the life quality of the patient 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 are set by the division of rheumatology of the Chinese medical society in 2010 (the reference: the division of rheumatology of the Chinese medical society, the guidelines for arthritis diagnosis and treatment [ J ]. the journal of Chinese rheumatology 2010, 6, 14, 416-419), indicate that OA drug therapy is mainly divided into drugs for controlling symptoms, drugs for improving disease conditions and chondroprotective agents. The clinically common 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 in 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 has effects of reducing activity of matrix protease and collagenase, relieving inflammation and pain, protecting articular cartilage, and delaying OA development. The existing medicine generally has slow effect, needs several weeks for treatment and begins 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; Surh and Lee, 1995). 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 (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. 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. No capsaicin injection is on the market at present.
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 CN200810154094.2 discloses a capsaicin beta-cyclodextrin inclusion compound and liposome and gel of the inclusion compound. This patent document uses beta-cyclodextrin to coat capsaicin to improve its water solubility and stability, thereby improving its bioavailability and reducing capsaicin irritation to some extent. The capsaicin cyclodextrin inclusion compound can be further prepared into liposome or gel. However, the inclusion compound needs to use organic solvent ethanol or benzyl alcohol or polyethylene glycol 400, and the preparation process is complicated.
At present, the applications of capsaicin preparations reported in published documents are still mainly for external use, and the capsaicin preparations are only injectable for local injection, and organic solvents such as polyethylene glycol, ethanol and the like are used in the injections, and have certain stimulation effects on blood vessels, skin, respiratory mucosa, conjunctiva and the like to trigger anaphylactic reaction; the toxic encephalopathy can be caused even by contacting with high-concentration organic solvents, the contact person shows dizziness, headache, different degrees of consciousness disorder and even coma, each organic solvent also has special damage effect or organ harmfulness, and great safety problems exist in clinical medication.
Disclosure of Invention
The invention provides a brand-new capsaicin fat emulsion which is uniform and clear, has a simple preparation process, is easy to amplify, not only effectively improves the solubility and stability of capsaicin, but also can reduce the side effect to a certain extent. The fat emulsion can be applied to local or systemic administration to treat various types of pain, and has a wide application range, and the specific invention is as follows:
the invention provides a capsaicin fat milk, which comprises capsaicin, oil for injection and phospholipid, wherein the content of the oil for injection in the final milk of the emulsion is 6-20% (w/v), preferably 10-15% (w/v) as an illustration, the content of the oil for injection can be 6%, 6.5%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, and the emulsion does not contain an organic solvent.
The oil for injection according to the present invention is one or more of soybean oil, sesame oil, tea oil, olive oil, corn oil, coconut oil, castor oil, fish oil, ethyl oleate, acetylated monoglyceride, glyceryl linoleate, and medium chain glycerides, preferably medium chain glycerides, wherein the medium chain glycerides are medium chain monoglycerides, medium chain diglycerides, or medium chain triglycerides, and in certain embodiments the oil for injection is medium chain triglycerides.
The phospholipid of the invention contains 80% or more of Phosphatidylcholine (PC), and is selected from egg yolk lecithin, soybean lecithin, hydrogenated soybean phospholipid, hydrogenated glycerophospholipid or lecithin obtained by synthesis and semisynthesis. Wherein, the preferred yolk lecithin or the refined yolk lecithin with higher phospholipid content is the yolk lecithin, wherein the content of the phospholipid in the fat milk is 0.5-3.0% (w/v), preferably 1.0-1.5% (w/v).
Further, the phospholipids according to the invention have a content of phosphatidylcholine in the range of 80% to 98% (w/w), and in some embodiments the phospholipids used according to the invention comprise Phosphatidylethanolamine (PE) in addition to phosphatidylcholine, wherein the content of phosphatidylethanolamine in the phospholipids is greater than 12% (w/w), preferably 12% to 18% phosphatidylethanolamine.
Further, the phospholipid contains Phosphatidylcholine (PC) and Phosphatidylethanolamine (PE), wherein the content of the phosphatidylcholine is greater than or equal to 80%, the content of the phosphatidylethanolamine is greater than 12%, and further preferably, the content of the phosphatidylcholine in the phospholipid is 80% -98%, and the content of the phosphatidylethanolamine is 12% -18%.
The phospholipid of the present invention may contain a small amount of other phospholipids in addition to PC and PG, for example, sphingomyelin, phosphatidylinositol, phosphatidylpolyglycerol, phosphatidylethylene glycol, phosphatidylpolyethylene glycol, and at least one of lyso, lyso PC, and lyso PG thereof, and the naturally-occurring phospholipid may contain components such as triglycerol and cholesterol in addition to the phospholipid.
In some embodiments, the final concentration of the drug solution is 0.1mg/ml to 2mg/ml, and may be, by way of example only, 0.1mg/ml, 0.5mg/ml, 1mg/ml, 1.5mg/ml, or 2 mg/ml.
In the present invention, the fat milk may further comprise an osmotic pressure regulator, wherein the content of the osmotic pressure regulator is 2% -2.75% (w/v), preferably 2.25% -2.5% (w/v), and the osmotic pressure regulator may be glycerol or concentrated glycerol.
In the present invention, the fat milk contains water, and in some embodiments, water for injection or ultrapure water is used.
The capsaicin fat emulsion provided by the invention comprises the following components:
0.20-0.41 part of capsaicin
12.00 to 40.38 portions of oil for injection
Lecithin 2.4 parts
5.0 parts of osmotic pressure regulator
A proper amount of water.
In the present invention, as one embodiment, the fat milk is composed of
Capsaicin 0.20 part
19.99 parts of medium chain triglyceride
Lecithin 2.40 parts
5.01 parts of concentrated glycerol
A proper amount of water;
or is made of
Capsaicin 0.20 part
19.99 parts of medium chain triglyceride
Lecithin 2.40 parts
5.01 parts of concentrated glycerol
A proper amount of water;
or is made of
Capsaicin 0.41 part
12.00 parts of medium chain triglyceride
Lecithin 2.39 parts
5.01 parts of concentrated glycerol
A proper amount of water;
or is made of
Capsaicin 0.40 part
30.51 parts of medium chain triglyceride
Lecithin 2.40 parts
5.00 parts of concentrated glycerol
A proper amount of water;
or is made of
Capsaicin 0.41 part
40.38 parts of medium chain triglyceride
Lecithin 2.39 parts
Concentrated glycerin 5.08 parts
And (4) proper amount of water.
The final emulsion has an average particle size of less than 300nm, preferably less than 270nm, and in certain embodiments the emulsion has an average particle size of less than 200 nm.
The fat emulsion can be used for local external application and can also be used for injection.
The capsaicin fat emulsion provided by the invention can be suitable for local injection or intravenous injection to treat various pain diseases.
The capsaicin fat emulsion provided by the invention can be used for injecting the joint cavity as one embodiment.
The invention provides a method for preparing the capsaicin fat milk, which comprises the following steps:
putting phospholipid and oil for injection into a container, heating, stirring and dissolving to obtain an oil solution 1;
adding capsaicin solid into the prepared oil solution 1, and stirring and dissolving to obtain an oil phase 2;
adding osmotic pressure regulator into water, stirring for dissolving to obtain water phase 3, and preheating;
slowly introducing oil phase 2 into water phase 3 under high speed shearing condition to obtain coarse emulsion
Homogenizing the crude milk under high pressure to obtain refined milk;
filtering refined milk to obtain final milk;
and (5) filling and sterilizing the final milk.
In the preparation method of the present invention, wherein the heating temperature in the step (1) may be 60 to 90 ℃, preferably 65 to 75 ℃, as an exemplary illustration, the heating temperature may be 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, and in some embodiments, preferably 70 ℃.
In the preparation method of the present invention, wherein the preheating temperature in the step (3) may be 55 to 85 ℃, preferably 60 to 70 ℃, as an exemplary illustration, the heating temperature may be 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, and in some embodiments, preferably 65 ℃.
In the preparation method of the present invention, wherein the high shear rate in step (4) is 1000-10000rpm/min, preferably 5000-10000 rpm/min, in some embodiments the shear rate is 5000 rpm/min.
In the preparation method, the high-pressure homogenizing primary pressure in the step (5) is 40-120 bar, preferably 70-80 bar; the secondary pressure is 400-1200bar, preferably 700-800bar, and the cycle time is 6-12, preferably 8.
In the preparation method of the invention, the filtration mode in the step (6) is membrane filtration, and the microporous membrane required for filtration is 0.22 μm, 0.45 μm, 0.65 μm, 0.80 μm PES or PVDF membrane, preferably 0.22 μm PVDF membrane.
In the preparation method, the sterilization mode in the step (7) is sterilization at 115-121 ℃ for 8-45min, preferably sterilization at 115-45 min or sterilization at 121 ℃ for 8-30min, more preferably sterilization at 121 ℃ for 15-30 min, and most preferably sterilization at 121 ℃ for 20 min.
In the present invention, as one embodiment, the method further comprises: putting phospholipid and oil for injection into a container according to the prescription amount, heating, stirring and dissolving to obtain an oil solution; adding a prescribed amount of capsaicin into the prepared oil solution, and stirring for dissolving; adding concentrated glycerol into water, stirring for dissolving to obtain water phase, and preheating; slowly introducing the oil phase into water under the condition of high-speed shearing to obtain coarse emulsion; homogenizing the crude milk under high pressure to obtain refined milk; filtering the refined milk with 0.22um filter membrane to obtain final milk; and (5) filling the final milk, and sterilizing at 121 ℃ for 20min to obtain the milk.
The invention uses a preparation process of high-speed shearing, the shearing speed can influence the drug content of the final emulsion in the preparation process, the high-speed shearing speed is 1000-10000rpm/min, preferably 5000-10000 rpm/min, and the shearing speed used in some embodiments is 5000 rpm/min.
The invention provides a homogeneous and clear fat emulsion containing capsaicin, which has high capsaicin content and strong stability, and the preparation method comprises the following steps:
putting phospholipid and oil for injection into a container, heating, stirring and dissolving to obtain an oil solution 1;
adding capsaicin solid into the prepared oil solution 1, and stirring and dissolving to obtain an oil phase 2;
adding osmotic pressure regulator into water, stirring for dissolving to obtain water phase 3, and preheating;
slowly introducing oil phase 2 into water phase 3 under high speed shearing condition to obtain coarse emulsion
Homogenizing the crude milk under high pressure to obtain refined milk;
filtering the refined milk to obtain final milk;
and (5) final milk filling and sterilization.
Wherein the oil for injection in step (1) is one or more of soybean oil, sesame oil, tea oil, olive oil, corn oil, coconut oil, castor oil, fish oil, ethyl oleate, acetylated monoglyceride, linoleic acid glyceride, and medium chain glyceride, preferably medium chain glyceride, wherein the medium chain glyceride is medium chain monoglyceride, medium chain diglyceride, or medium chain triglyceride, and in some embodiments the oil for injection is medium chain triglyceride;
the phospholipid is Phosphatidylcholine (PC) with content of 80% or more, and is selected from egg yolk lecithin, soybean lecithin, hydrogenated soybean phospholipid, hydrogenated glycerol phospholipid or lecithin obtained by synthesis or semisynthesis. Wherein, the preferred yolk lecithin or the refined yolk lecithin with higher phospholipid content is the yolk lecithin, wherein the content of the phospholipid in the fat milk is 0.5-3.0% (w/v), preferably 1.0-1.5% (w/v).
Said heating temperature described in step (1) may be 60-90 ℃, preferably 65-75 ℃, as an illustrative example, the heating temperature may be 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, and in certain embodiments preferably 70 ℃.
Wherein the osmotic pressure regulator in step (3) is glycerol or concentrated glycerol, wherein the pre-heating temperature may be 55-85 deg.C, preferably 60-70 deg.C, and illustratively, the heating temperature may be 55 deg.C, 60 deg.C, 65 deg.C, 70 deg.C, 75 deg.C, 80 deg.C, 85 deg.C, and in certain embodiments, preferably 65 deg.C.
Wherein the high speed shearing speed in step (4) is 10000rpm/min, preferably 5000rpm/min-10000 rpm/min, and in some embodiments the shearing speed is 5000 rpm/min.
Wherein the high-pressure homogenizing primary pressure in the step (5) is 40-120 bar, preferably 70-80 bar; the secondary pressure is 400-1200bar, preferably 700-800bar, and the cycle time is 6-12 times, preferably 8 times.
Wherein the filtration mode in the step (6) is membrane filtration, and the microporous membrane required by the filtration is PES or PVDF membrane with the diameter of 0.22 μm, 0.45 μm, 0.65 μm or 0.80 μm, and is preferably PVDF membrane with the diameter of 0.22 μm.
Wherein the sterilization mode in the step (7) is sterilization at 115-121 ℃ for 8-45min, preferably sterilization at 115-45 min or 121 ℃ for 8-30min, more preferably sterilization at 121 ℃ for 15-30 min, and most preferably sterilization at 121 ℃ for 20 min.
The resulting solution may have a drug concentration of 0.1-2.0 mg/ml, with a concentration of 0.1mg/ml, 0.5mg/ml, 1mg/ml, 1.5mg/ml, or 2mg/ml being possible as illustrative examples.
The emulsion obtained in the present invention has an average particle diameter of less than 300nm, more preferably less than 200 nm.
The invention has the advantages that:
the brand new capsaicin fat emulsion is free of any organic solvent, uniform and stable in preparation, and capable of effectively improving the solubility and stability of capsaicin and improving the bioavailability of the capsaicin;
the production process is mature and stable; the application range is expanded, the medicine can be locally externally used, can be injected for use, and can be applied to various pain diseases.
The capsaicin fat emulsion expands the use mode of the current capsaicin product, and can be locally externally used and also used by injection; meanwhile, the fat emulsion effectively solves the problem of irritation of the capsaicin, better utilizes the analgesic effect of the capsaicin, and enables the capsaicin to be applied to more pain diseases.
The invention solves the problems of the solubility and the stability of the capsaicin fat emulsion by screening the type and the content of the oil for injection and further improving the process method, prepares the capsaicin fat emulsion which can be used externally or injected on the premise of ensuring the safety and reducing the irritation, provides a clear prescription composition, has simple prescription composition, performs preparation stability investigation, shows that the preparation has good stability by the investigation result, and can effectively ensure the clinical medication safety.
Detailed Description
The following examples and experimental examples are intended to further illustrate the present invention, but are not intended to limit the scope of the invention in any way.
Example 1: capsaicin fat emulsion injection
Prescription composition and physicochemical properties
The preparation method comprises the following steps: putting yolk lecithin PL-100 (a type of yolk lecithin containing 80% of Phosphatidylcholine (PC) and 15% of Phosphatidylethanolamine (PE) and medium-chain triglyceride into a container according to a prescription amount, heating and stirring at 70 ℃ to dissolve to obtain an oil solution, adding capsaicin solid according to the prescription amount into the prepared oil solution, adding capsaicin solid at 70 ℃ to stir to dissolve, adding concentrated glycerol into water to stir to dissolve to obtain a water phase, preheating at 65 ℃, slowly introducing an oil phase into water under a high-speed shearing condition (5000 rpm/min) to obtain crude milk, homogenizing the crude milk under high pressure (750 bar) to obtain refined milk, filtering the refined milk (0.22 mu m, a PVDF filter membrane) to obtain final milk, filling the final milk (5 ml), and sterilizing (121 ℃ and 20 min) to obtain the finished product.
And (3) analysis: the actual content is close to the theoretical value, the physical and chemical indexes meet the basic requirements of the injection, the properties are stable, and no drug crystal is separated out when the injection is placed at low temperature and normal temperature.
Example 2: capsaicin fat emulsion injection
Prescription composition and physicochemical properties
The preparation method comprises the following steps: placing yolk lecithin PL-100 and medium-chain triglyceride into a container according to the prescription amount, heating at 70 ℃, stirring and dissolving to obtain an oil solution; adding the capsaicin solid with the prescription amount into the prepared oil solution, adding the capsaicin solid at 70 ℃, and stirring to dissolve the capsaicin solid. Adding concentrated glycerol into water, stirring to dissolve to obtain water phase, and preheating at 65 deg.C; slowly introducing the oil phase into water under high-speed shearing condition (5000 rpm/min) to obtain coarse emulsion; homogenizing the crude milk under high pressure (750 bar) to obtain refined milk; filtering the refined milk (0.22 um, PVDF filter membrane) to obtain final milk; filling the final milk into a container (5 ml), and sterilizing at 121 deg.C for 20 min.
And (3) analysis: the actual content is close to the theoretical value, the physical and chemical indexes meet the basic requirements of the injection, the properties are stable, and no drug crystal is separated out when the injection is placed at low temperature and normal temperature.
Example 3: capsaicin fat emulsion injection
1) Prescription composition and physicochemical properties
The preparation method comprises the following steps: placing egg yolk lecithin PL-100 and soybean oil in a container according to the prescription amount, heating and stirring at 70 ℃ to dissolve to obtain an oil solution; adding the capsaicin solid with the prescription amount into the prepared oil solution, adding the capsaicin solid at 70 ℃, and stirring to dissolve the capsaicin solid. Adding concentrated glycerol into water, stirring for dissolving to obtain water phase, and preheating at 65 deg.C; slowly introducing the oil phase into water under high-speed shearing condition (5000 rpm/min) to obtain coarse emulsion; homogenizing the crude milk under high pressure (750 bar) to obtain refined milk; filtering the refined milk (0.22 um, PVDF filter membrane) to obtain final milk; filling the final milk (5 ml), and sterilizing (121 deg.C, 20 min).
And (3) analysis: when the actual content is close to the theoretical value, the physical and chemical indexes meet the basic requirements of the injection, no drug crystal is separated out when the injection is placed at low temperature and normal temperature, but the emulsion has the wall hanging phenomenon compared with the examples 1 and 2.
Example 4: capsaicin fat emulsion injection
Prescription composition and physicochemical properties
The preparation method comprises the following steps: placing yolk phospholipid PL-100 and soybean oil in a container according to the prescription amount, heating at 70 ℃, stirring and dissolving to obtain an oil solution; adding the capsaicin solid with the prescription amount into the prepared oil solution, and adding the capsaicin solid at 70 ℃ for stirring and dissolving. Adding concentrated glycerol into water, stirring to dissolve to obtain water phase, and preheating at 65 deg.C; slowly introducing the oil phase into water under high-speed shearing condition (5000 rpm/min) to obtain coarse emulsion; homogenizing the crude milk under high pressure (750 bar) to obtain refined milk; filtering refined milk (0.22 um, PVDF filter membrane) to obtain final milk; filling the final milk into a container (5 ml), and sterilizing at 121 deg.C for 20 min.
And (3) analysis: when the actual content is close to the theoretical value, the physical and chemical indexes meet the basic requirements of the injection, and no drug crystal is precipitated after the injection is placed at low temperature and normal temperature. However, the emulsion showed wall build-up as compared with examples 1 and 2, and the properties were similar to those of example 3.
Example 5: capsaicin fat emulsion injection
Formulation composition and physical and chemical properties
The preparation method comprises the following steps: placing yolk lecithin PL-100 and medium-chain triglyceride into a container according to the prescription amount, heating at 70 ℃, stirring and dissolving to obtain an oil solution; adding the capsaicin solid with the prescription amount into the prepared oil solution, adding the capsaicin solid at 70 ℃, and stirring to dissolve the capsaicin solid. Adding concentrated glycerol into water, stirring to dissolve to obtain water phase, and preheating at 65 deg.C; slowly introducing the oil phase into water under high-speed shearing condition (5000 rpm/min) to obtain coarse milk; homogenizing the crude milk under high pressure (750 bar) to obtain refined milk; filtering the refined milk (0.22 um, PVDF filter membrane) to obtain final milk; filling the final milk (5 ml), and sterilizing (121 deg.C, 20 min).
And (3) analysis: the actual content is close to the theoretical value, the physical and chemical indexes meet the basic requirements of the injection, the properties are stable, and no drug crystal is separated out when the injection is placed at low temperature and normal temperature.
Example 6: capsaicin fat emulsion injection
Prescription composition and physicochemical properties
The preparation method comprises the following steps: placing egg yolk lecithin PL-100 and medium-chain triglyceride into a container according to the prescription amount, heating and stirring at 70 ℃ to dissolve to obtain an oil solution; adding the capsaicin solid with the prescription amount into the prepared oil solution, and adding the capsaicin solid at 70 ℃ for stirring and dissolving. Adding concentrated glycerol into water, stirring to dissolve to obtain water phase, and preheating at 65 deg.C; slowly introducing the oil phase into water under high-speed shearing condition (5000 rpm/min) to obtain coarse emulsion; homogenizing the crude milk under high pressure (750 bar) to obtain refined milk; filtering the refined milk (0.22 um, PVDF filter membrane) to obtain final milk; filling the final milk (5 ml), and sterilizing (121 deg.C, 20 min).
And (3) analysis: the actual content is close to the theoretical value, the physical and chemical indexes meet the basic requirements of the injection, the properties are stable, and no drug crystal is separated out when the injection is placed at low temperature and normal temperature.
Example 7: capsaicin fat emulsion injection
Formulation composition and physical and chemical properties
The preparation method comprises the following steps: placing egg yolk lecithin PL-100 and medium-chain triglyceride into a container according to the prescription amount, heating and stirring at 70 ℃ to dissolve to obtain an oil solution; adding the capsaicin solid with the prescription amount into the prepared oil solution, and adding the capsaicin solid at 70 ℃ for stirring and dissolving. Adding concentrated glycerol into water, stirring to dissolve to obtain water phase, and preheating at 65 deg.C; slowly introducing the oil phase into water under high-speed shearing condition (5000 rpm/min) to obtain coarse milk; homogenizing the crude milk under high pressure (750 bar) to obtain refined milk; filtering refined milk (0.22 um, PVDF filter membrane) to obtain final milk; filling the final milk into a container (5 ml), and sterilizing at 121 deg.C for 20 min.
And (3) analysis: the actual content is close to the theoretical value, the physical and chemical indexes meet the basic requirements of the injection, the properties are stable, and no drug crystal is separated out when the injection is placed at low temperature and normal temperature.
Example 8
Egg yolk lecithin E80 (about 80% Phosphatidylcholine (PC) content, about 15% Phosphatidylethanolamine (PE) content, Lipoid, Germany) was used as an emulsifier;
formulation composition and physical and chemical properties
The preparation method comprises the following steps: placing yolk lecithin E80 and medium-chain triglyceride into a container according to the prescription amount, heating and stirring at 70 ℃ to dissolve to obtain an oil solution; adding the capsaicin solid with the prescription amount into the prepared oil solution, and adding the capsaicin solid at 70 ℃ for stirring and dissolving. Adding concentrated glycerol into water, stirring for dissolving to obtain water phase, and preheating at 65 deg.C; slowly introducing the oil phase into water under high-speed shearing condition (5000 rpm/min) to obtain coarse emulsion; homogenizing the crude milk under high pressure (750 bar) to obtain refined milk; filtering the refined milk (0.22 um, PVDF filter membrane) to obtain final milk; filling the final milk into a container (5 ml), and sterilizing at 121 deg.C for 20 min.
And (3) analysis: the actual content is close to the theoretical value, the physical and chemical indexes meet the basic requirements of the injection, the properties are stable, and no drug crystal is precipitated when the injection is placed at low temperature and normal temperature. The yolk lecithin E80 has substantially similar components and contents to those of yolk lecithin PL-100, so that nano fat milk can be prepared.
Comparative example 1: capsaicin fat emulsion injection
Prescription composition and physicochemical properties
The preparation method comprises the following steps: placing yolk lecithin PL-100 and soybean oil in a container according to the prescription amount, heating at 70 ℃, stirring and dissolving to obtain an oil solution; adding the capsaicin solid with the prescription amount into the prepared oil solution, adding the capsaicin solid at 70 ℃, and stirring to dissolve the capsaicin solid. Adding concentrated glycerol into water, stirring for dissolving to obtain water phase, and preheating at 65 deg.C; slowly introducing the oil phase into water under high-speed shearing condition (10000 rpm/min) to obtain coarse milk; homogenizing the crude milk under high pressure (750 bar) to obtain refined milk; filtering the refined milk (0.22 um, PVDF filter membrane) to obtain final milk; filling the final milk (5 ml), and sterilizing (121 deg.C, 20 min).
And (3) analysis: in the process of preparing the coarse emulsion, when the high-speed shearing speed is increased from 5000 to 10000rpm/min, the actual content of the medicament is obviously lower than the theoretical value, and no medicament crystal is precipitated when the emulsion is placed at low temperature and normal temperature, but compared with examples 1 and 2, the emulsion has obvious wall hanging phenomenon and has similar properties with examples 3 and 4.
Comparative example 2: capsaicin fat emulsion injection
Prescription composition and physicochemical properties
The preparation method comprises the following steps: placing yolk lecithin PL-100 and soybean oil in a container according to the prescription amount, heating at 70 ℃, stirring and dissolving to obtain an oil solution; adding the capsaicin solid with the prescription amount into the prepared oil solution, and adding the capsaicin solid at 70 ℃ for stirring and dissolving. Adding concentrated glycerol into water, stirring to dissolve to obtain water phase, and preheating at 65 deg.C; slowly introducing the oil phase into water under high-speed shearing condition (10000 rpm/min) to obtain coarse milk; homogenizing the crude milk under high pressure (750 bar) to obtain refined milk; filtering the refined milk (0.22 um, PVDF filter membrane) to obtain final milk; filling the final milk (5 ml), and sterilizing (121 deg.C, 20 min).
And (3) analysis: in the course of preparing coarse emulsion, when the high-speed shearing speed is raised to 10000rpm/min from 5000, the actual content of medicine is obviously less than theoretical value, and when the concentration of emulsion is greater, the medicine crystal can be separated out by placing at low temp. and normal temp., and the emulsion is not stable under the above-mentioned concentration.
Comparative example 3: capsaicin fat emulsion injection
Prescription composition and physicochemical properties
The preparation method comprises the following steps: placing yolk lecithin PL-100 and medium-chain triglyceride into a container according to the prescription amount, heating at 70 ℃, stirring and dissolving to obtain an oil solution; adding the capsaicin solid with the prescription amount into the prepared oil solution, adding the capsaicin solid at 70 ℃, and stirring to dissolve the capsaicin solid. Adding concentrated glycerol into water, stirring to dissolve to obtain water phase, and preheating at 65 deg.C; slowly introducing the oil phase into water under high-speed shearing condition (5000 rpm/min) to obtain coarse emulsion.
Comparative example 4: capsaicin fat emulsion injection
Prescription composition and physicochemical properties
The preparation method comprises the following steps: placing yolk lecithin PL-100 and medium-chain triglyceride into a container according to the prescription amount, heating at 70 ℃, stirring and dissolving to obtain an oil solution; adding the capsaicin solid with the prescription amount into the prepared oil solution, and adding the capsaicin solid at 70 ℃ for stirring and dissolving. Adding concentrated glycerol into water, stirring for dissolving to obtain water phase, and preheating at 65 deg.C; slowly introducing the oil phase into water under high-speed shearing condition (5000 rpm/min) to obtain coarse emulsion.
Comparative example 5:
egg yolk lecithin PC-98T (japan bikul corporation, Phosphatidylcholine (PC) content > 98%) was used as an emulsifier;
formulation composition and physical and chemical properties
The preparation method comprises the following steps: placing yolk lecithin PC-98T and medium-chain triglyceride into a container according to the prescription amount, heating at 70 ℃, stirring and dissolving to obtain an oil solution; adding the capsaicin solid with the prescription amount into the prepared oil solution, adding the capsaicin solid at 70 ℃, and stirring to dissolve the capsaicin solid. Adding concentrated glycerol into water, stirring for dissolving to obtain water phase, and preheating at 65 deg.C; slowly introducing the oil phase into water under high-speed shearing condition (5000 rpm/min) to obtain coarse emulsion.
And (3) analysis: the crude emulsion can not be formed uniformly, the oil-water separation phenomenon is obvious, and a large amount of emulsion drops are gathered into a mass.
Comparative example 6:
hydrogenated soy lecithin HSPC (phosphatidylcholine (PC) purity about 99%) was used as emulsifier;
formulation composition and physical and chemical properties
The preparation method comprises the following steps: hydrogenated soybean lecithin HSPC and medium-chain triglyceride are placed in a container according to the prescription amount, and are heated and stirred at 70 ℃ to be dissolved.
And (3) analysis: the medium chain triglycerides are not capable of dissolving hydrogenated soy lecithin HSPC.
Experimental example 1: examination of adsorption on a Filter Membrane
The capsaicin nanoemulsion solutions of comparative example 1 and comparative example 2 were examined for adsorption on a filter membrane (PVDF material, 0.22um pore size), and the change in drug content before and after filtration was examined;
summarizing and explaining: the content of the drug is not obviously changed before and after filtration, which indicates that the PVDF material filter membrane can not adsorb the drug.
Experimental example 2: investigation of sterilization
The capsaicin nanoemulsion solution of different embodiments is examined for sterilization stability, the solution is placed in a high-temperature steam sterilization pot and sterilized for 20 minutes at 121 ℃, and the change of the content is examined;
summarizing and explaining: before and after sterilization, the emulsion has stable properties, the API content basically does not change, and the quality requirement is met.
Experimental example 3 consideration of stability of influence factors
Performing primary influence factor stability investigation (illumination, high temperature and freeze thawing) on the capsaicin fat emulsion injection with 2mg/ml of different oil phases (soybean oil/medium chain triglyceride), analyzing unstable factors of the product, determining key influence conditions, and providing reference basis for formulation of storage, packaging and transportation conditions and validity period of subsequent products;
summarizing and explaining: the product is placed at 40 ℃ for 15 days, the content of the two prescriptions has no obvious change, and the character is stable. When the mixture is placed at the temperature of 60 ℃ for 15 days, the content of the example 7 is obviously reduced, while the content of the example 8 is basically unchanged. The two formulas have stable properties at 60 ℃;
the illumination has great influence on the stability of the preparation, the content of the medicament is obviously reduced under the condition of no package, the medicament degradation is obviously inhibited after the package is added, but the character is not obviously changed. After freezing and thawing, the emulsion has delamination phenomenon, and the delamination is more obvious in example 7.
Experimental example 4 preparation stability experiment
The samples of example 7 and example 8 were subjected to stability examination at 2-8 deg.C, and sampled at different times for analysis of content, properties, particle size, and polydispersity index, and the results are shown below:
and (4) conclusion: after the sample is placed for 2 months at the temperature of 2-8 ℃, the sample content of the samples of the prescription 1 and the prescription 2 has good stability, and the content, the character, the grain diameter and the polydispersity index have no obvious change.
Claims (18)
1. A capsaicin fat emulsion contains capsaicin, oil for injection and phospholipid, wherein,
(1) the oil for injection is medium chain glyceride, and the content of the medium chain glyceride is 6-20% (w/v);
(2) the phospholipid contains 80% or more of phosphatidylcholine, and the content of the phospholipid in the fat milk is 0.5-3.0% (w/v).
2. Fat milk according to claim 1, characterized in that the content of medium chain glycerides is 10-15% (w/v).
3. Fat milk according to claim 1, wherein the medium chain glycerides are selected from medium chain mono-, di-or triglycerides, in combination with one or more other medium chain glycerides.
4. The fat milk according to claim 1, wherein the phospholipid is soybean lecithin, egg yolk lecithin, refined egg yolk lecithin, hydrogenated soybean lecithin or hydrogenated glycerophospholipid, preferably egg yolk lecithin or refined egg yolk lecithin.
5. The fat milk of claim 1, wherein the phospholipid comprises phosphatidylcholine in an amount of 80% to 98%.
6. A fat milk according to claim 5, characterized in that the phospholipids further comprise phosphatidylethanolamine in an amount of more than 12%.
7. Fat milk according to claim 1, characterized in that the content of phospholipids is 1.0-1.5% (w/v).
8. Fat milk according to claim 1, characterized in that the capsaicin is present in an amount of 0.05-0.5% (w/v), preferably 0.1-0.2% (w/v).
9. The fat milk according to claim 1, wherein the fat milk comprises an osmotic pressure regulator and water, wherein the osmotic pressure regulator is selected from glycerol or concentrated glycerol, and the water is water for injection or ultrapure water.
10. Fat milk according to claim 1, characterized in that the fat milk is prepared from
0.20-0.41 part of capsaicin
12.00 to 40.38 portions of oil for injection
Lecithin 2.40 parts
5.00 parts of osmotic pressure regulator
The right amount of water.
11. Fat milk according to claim 1, characterized in that the fat milk is prepared from
Capsaicin 0.20 part
19.99 parts of medium chain triglyceride
Lecithin 2.40 parts
5.01 parts of concentrated glycerol
A proper amount of water;
or is made of
Capsaicin 0.20 part
19.99 parts of medium chain triglyceride
Lecithin 2.40 parts
5.01 parts of concentrated glycerol
A proper amount of water;
or is made of
Capsaicin 0.41 part
12.00 parts of medium chain triglyceride
Lecithin 2.39 parts
5.01 parts of concentrated glycerol
A proper amount of water;
or is made of
Capsaicin 0.40 part
30.51 parts of medium chain triglyceride
Lecithin 2.40 parts
Concentrated glycerol 5.00 parts
A proper amount of water;
or is made of
Capsaicin 0.41 part
Medium chain triglyceride 40.38 parts
Lecithin 2.39 parts
Concentrated glycerin 5.08 parts
The right amount of water.
12. The fat emulsion according to claim 1, wherein the fat emulsion is suitable for topical application or for injection, and the injection is suitable for topical injection or intravenous injection.
13. Fat milk according to claims 1-12, characterized in that the fat milk is prepared by high speed shearing with a shearing speed of 1000-10000rpm/min, preferably 5000-10000 rpm/min.
14. A fat milk according to any of claims 1-12, characterized in that the capsaicin fat milk is prepared as follows:
(1) putting phospholipid and oil for injection into a container, heating, stirring and dissolving to obtain an oil solution 1;
(2) adding capsaicin solid into the prepared oil solution 1, and stirring and dissolving to obtain an oil phase 2;
(3) adding osmotic pressure regulator into water, stirring for dissolving to obtain water phase 3, and preheating;
(4) slowly introducing oil phase 2 into water phase 3 under high speed shearing condition to obtain coarse emulsion
(5) Homogenizing the crude milk under high pressure to obtain refined milk;
(6) filtering the refined milk to obtain final milk;
(7) and (5) filling and sterilizing the final milk.
15. Fat milk according to claim 11, characterized in that the heating temperature in step (1) is 60-90 ℃, preferably 65-75 ℃;
the preheating temperature in the step (3) can be 55-85 ℃, and preferably 60-70 ℃;
the high-speed shearing speed in the step (4) is 1000-10000rpm/min, preferably 5000-10000 rpm/min;
the primary pressure of the high-pressure homogenization in the step (5) is 40-120 bar, preferably 70-80 bar; the secondary pressure is 400-1200bar, preferably 700-800bar, and the cycle time is 6-12 times, preferably 8 times;
the filtration mode in the step (6) is membrane filtration, and the microporous membrane required by the filtration is a PES or PVDF membrane with the diameter of 0.22 μm, 0.45 μm, 0.65 μm or 0.80 μm, preferably a PVDF membrane with the diameter of 0.22 μm;
the sterilization mode in the step (7) is sterilization at 115-121 ℃ for 8-45min, preferably sterilization at 115-45 min or sterilization at 121 ℃ for 8-30min, more preferably sterilization at 121 ℃ for 15-30 min, and most preferably sterilization at 121 ℃ for 20 min.
16. The fat milk of claim 11, wherein the method further comprises: putting phospholipid and oil for injection into a container according to the prescription amount, heating, stirring and dissolving to obtain an oil solution; adding a prescribed amount of capsaicin into the prepared oil solution, and stirring for dissolving; adding concentrated glycerol into water, stirring for dissolving to obtain water phase, and preheating; slowly introducing the oil phase into water under the condition of high-speed shearing to obtain coarse emulsion; homogenizing the crude milk under high pressure to obtain refined milk; filtering the refined milk with 0.22um filter membrane to obtain final milk; and filling the final milk, and sterilizing at 121 ℃ for 20min to obtain the milk.
17. Fat emulsion according to any one of claims 1-16, characterised in that the drug concentration of the emulsion is 0.1-2.0 mg/ml.
18. A fat emulsion according to any one of claims 1-16, characterized in that the average particle size of the emulsion is less than 300nm, preferably less than 270 nm.
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| CN202110180761.XA CN114903851A (en) | 2021-02-10 | 2021-02-10 | Capsaicin fat emulsion |
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| CN202110180761.XA CN114903851A (en) | 2021-02-10 | 2021-02-10 | Capsaicin fat emulsion |
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