CN114668779A - Therapeutic use of acellular fat extracts for erectile dysfunction - Google Patents
Therapeutic use of acellular fat extracts for erectile dysfunction Download PDFInfo
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- CN114668779A CN114668779A CN202011547887.8A CN202011547887A CN114668779A CN 114668779 A CN114668779 A CN 114668779A CN 202011547887 A CN202011547887 A CN 202011547887A CN 114668779 A CN114668779 A CN 114668779A
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- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
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- A—HUMAN NECESSITIES
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The present invention relates to the therapeutic use of acellular fat extracts for erectile dysfunction. In particular, the present invention provides the use of a cell-free fat extract for the preparation of a composition or formulation for one or more uses selected from the group consisting of: (i) prevention and/or treatment of erectile dysfunction; (ii) preventing and/or treating cavernous nerve injury of penis. The acellular fat extract of the present invention has excellent therapeutic effects on erectile dysfunction and cavernous nerve injury of the penis.
Description
Technical Field
The invention relates to the field of medicines, in particular to application of an acellular fat extract to treatment of erectile dysfunction.
Background
Male Erectile Dysfunction (ED) is a pathological condition in which a male is unable to complete sexual intercourse and satisfactory sexual activity due to persistent or recurrent episodes in which penile erection is difficult to achieve and maintain.
The Cavernous nerve of the penis (CN) is the major nerve inducing penile erection, and various causes of CN injury contribute to neurogenic penile erection dysfunction (NED). For example, CN is easily damaged by pelvic surgery such as radical prostate cancer surgery, which causes postoperative NED. However, the prior art lacks effective therapeutic drugs for erectile dysfunction caused by injury of the cavernous nerve of the penis, thereby limiting effective treatment of patients with erectile dysfunction.
Therefore, there is a need in the art to develop a drug effective for treating erectile dysfunction caused by injury to the cavernous nerve of the penis.
Disclosure of Invention
The invention aims to provide application of a cell-free fat extract in preventing and/or treating erectile dysfunction and cavernous nerve injury of the penis.
In a first aspect of the invention, there is provided the use of a cell-free fat extract for the preparation of a composition or formulation for one or more uses selected from the group consisting of: (i) prevention and/or treatment of erectile dysfunction; (ii) preventing and/or treating cavernous nerve injury of penis.
In another preferred embodiment, the erectile dysfunction is male erectile dysfunction.
In another preferred embodiment, the erectile dysfunction includes erectile dysfunction caused by injury to the cavernous nerve of the penis.
In another preferred embodiment, the cell-free fat extract is obtained by extracting fat from human or non-human mammal.
In another preferred embodiment, the non-human mammal is a monkey, chimpanzee, cow, pig, dog, sheep, mouse, or rabbit.
In another preferred embodiment, the composition or formulation comprises a pharmaceutical composition or formulation, a food composition or formulation, a nutraceutical composition or formulation, or a dietary supplement.
In another preferred embodiment, the composition or preparation further comprises a pharmaceutically, food, health product or dietary acceptable carrier.
In another preferred embodiment, the composition or the preparation is in the form of oral preparation, external preparation or injection preparation.
In another preferred embodiment, the injection preparation is intravenous injection or intramuscular injection.
In another preferred embodiment, the injection preparation is a cavernous penis injection preparation.
In another preferred embodiment, the composition or formulation is in the form of a solid dosage form, a semi-solid dosage form, or a liquid dosage form, such as a solution, gel, cream, lotion, ointment, cream, paste, cake, powder, patch, and the like.
In another preferred embodiment, the composition or the preparation is in the form of powder, granules, capsules, injection, tincture, oral liquid, tablets or buccal tablets.
In another preferred embodiment, the composition or formulation is administered topically, or by injection.
In another preferred embodiment, the injection mode is cavernous penis injection.
In another preferred embodiment, the cell-free fat extract is cell-free and free of lipid droplets.
In another preferred embodiment, the fat droplets are oil droplets released after the fat cells are disrupted.
In another preferred embodiment, the term "free of fat droplets" means that the percentage of oil droplets in the cell-free fat extract is less than 1%, preferably less than 0.5%, more preferably less than 0.1% by volume of the total liquid.
In another preferred embodiment, the cell is selected from the group consisting of: endothelial cells, adipose-derived stem cells, macrophage cells, and stromal cells.
In another preferred embodiment, the term "cell-free" means that the average number of cells in 1ml of cell-free fat extract is less than or equal to 1, preferably less than or equal to 0.5, more preferably less than or equal to 0.1, or is 0.
In another preferred example, the cell-free fat extract is a naturally obtained nano fat extract without additional ingredients.
In another preferred embodiment, the term "free of added ingredients" means that no solution, solvent, small molecule, chemical, and biological additives are added during the preparation of the fat extract except for the rinsing step.
In another preferred embodiment, the cell-free fat extract is prepared by emulsifying fat tissue and centrifuging.
In another preferred embodiment, the cell-free fat extract comprises one or more components selected from the group consisting of: IGF-1, BDNF, GDNF, TGF-beta 1, HGF, bFGF, VEGF, TGF-beta 1, PDGF, EGF, NT-3, GH, G-CSF, or combinations thereof.
In another preferred embodiment, the one cell-free fat extract contains, but is not limited to, one or more components selected from the group consisting of: IGF-1, BDNF, GDNF, bFGF, VEGF, TGF- β 1, HGF, PDGF, or combinations thereof.
In another preferred example, the cell-free fat extract is a cell-free fat extract.
In another preferred embodiment, the concentration of IGF-1 in the cell-free fat extract is 5000-30000pg/ml, preferably 6000-20000pg/ml, more preferably 7000-15000pg/ml, more preferably 8000-12000pg/ml, more preferably 9000-11000pg/ml, more preferably 9500-10500 pg/ml.
In another preferred embodiment, the concentration of BDNF in the cell-free fat extract is 800-5000pg/ml, preferably 1000-4000pg/ml, more preferably 1200-2500pg/ml, more preferably 1400-2000pg/ml, more preferably 1600-2000pg/ml, more preferably 1700-1850 pg/ml.
In another preferred embodiment, the concentration of GDNF in the cell-free fat extract is 800-5000pg/ml, preferably 1000-4000pg/ml, more preferably 1200-2500pg/ml, more preferably 1400-2000pg/ml, more preferably 1600-2000pg/ml, more preferably 1700-1900 pg/ml.
In another preferred embodiment, the concentration of bFGF in the cell-free fat extract is 50-600pg/ml, preferably 100-500pg/ml, more preferably 120-400pg/ml, more preferably 150-300pg/ml, more preferably 200-280pg/ml, more preferably 220-260 pg/ml.
In another preferred embodiment, the concentration of VEGF in the cell-free fat extract is 50-500pg/ml, preferably 100-400pg/ml, more preferably 120-300pg/ml, more preferably 150-250pg/ml, more preferably 170-230pg/ml, more preferably 190-210 pg/ml.
In another preferred embodiment, the concentration of TGF-beta 1 in the cell-free fat extract is 200-3000pg/ml, preferably 400-2000pg/ml, more preferably 600-1500pg/ml, more preferably 800-1200pg/ml, more preferably 800-1100pg/ml, more preferably 900-1000 pg/ml.
In another preferred embodiment, the concentration of HGF in the cell-free fat extract is 200-3000pg/ml, preferably 400-2000pg/ml, more preferably 600-1500pg/ml, more preferably 600-1200pg/ml, more preferably 800-1000pg/ml, more preferably 850-950 pg/ml.
In another preferred embodiment, the concentration of PDGF in the cell-free fat extract is 50-600pg/ml, preferably 80-400pg/ml, more preferably 100-300pg/ml, more preferably 140-220pg/ml, more preferably 160-200pg/ml, more preferably 170-190 pg/ml.
In another preferred embodiment, the weight ratio of IGF-1 to VEGF is 20-100: 1, preferably 30-70: 1, more preferably 40 to 60: 1, optimally 45-55: 1.
in another preferred embodiment, the weight ratio of BDNF to VEGF is 2-20: 1, preferably 4-15: 1, more preferably 6 to 12: 1, optimally 8-9.5: 1.
in another preferred embodiment, the weight ratio of GDNF to VEGF is 2-20: 1, preferably 4-15: 1, more preferably 6-12: 1, optimally 8.5-9.5: 1.
in another preferred embodiment, the weight ratio of bFGF to VEGF is 0.2 to 8: 1, preferably 0.5 to 5: 1, more preferably 0.6 to 2: 1, more preferably 0.8 to 1.6: 1, optimally 1-1.5: 1.
in another preferred embodiment, the weight ratio of TGF-beta 1 to VEGF is 1-20: 1, preferably 1 to 15: 1, more preferably 1 to 10: 1, more preferably 2 to 8: 1, more preferably 4 to 6: 1.
in another preferred embodiment, the weight ratio of HGF to VEGF is 1-20: 1, preferably 1 to 15: 1, more preferably 1 to 10: 1, more preferably 2 to 8: 1, more preferably 4 to 5.5: 1.
in another preferred embodiment, the weight ratio of PDGF to VEGF is 0.1 to 3: 1, preferably 0.2-2: 1, more preferably 0.4 to 1.5: 1, optimally 0.7-1.2: 1.
in another preferred embodiment, the cell-free fat extract is prepared by the following method:
(1) providing an adipose tissue material, disrupting the adipose tissue material, and rinsing (e.g., with physiological saline) to obtain rinsed adipose tissue;
(2) centrifuging the rinsed adipose tissue to obtain a layered mixture;
(3) removing the upper oil layer and the lower water layer from the layered mixture, and collecting the middle layer (i.e., fat layer containing adipocytes);
(4) emulsifying the intermediate layer to obtain an emulsified fat mixture (also called nano-fat);
(5) centrifuging the emulsified fat mixture to obtain an intermediate liquid layer, namely a fat primary extract; and
(6) filtering and sterilizing the fat primary extract to obtain a cell-free fat extract.
In a second aspect of the present invention, there is provided a method for preparing a cell-free fat extract, the method comprising the steps of:
(1) providing an adipose tissue material, disrupting the adipose tissue material, and rinsing (e.g., with physiological saline) the disrupted adipose tissue material to obtain a rinsed adipose tissue;
(2) centrifuging the rinsed adipose tissue to obtain a layered mixture;
(3) removing the upper oil layer and the lower water layer from the layered mixture, and collecting the middle layer (i.e., fat layer containing adipocytes);
(4) emulsifying the intermediate layer to obtain an emulsified fat mixture (also called nano-fat);
(5) centrifuging the emulsified fat mixture to obtain an intermediate liquid layer, namely a fat primary extract; and
(6) filtering and sterilizing the fat primary extract to obtain a cell-free fat extract.
In another preferred embodiment, the cell-free fat extract is as described in the first aspect of the invention.
In another preferred embodiment, in the step (2), the centrifugation is performed at 2500 g-.
In another preferred embodiment, in the step (2), the centrifugation time is 1-15min, preferably 1-10min, more preferably 1-8min, and most preferably 1-5 min.
In another preferred embodiment, the temperature of the centrifugation is 2-6 ℃.
In another preferred embodiment, in the step (4), the emulsification is mechanical emulsification.
In another preferred embodiment, the mechanical emulsification is mechanical emulsification by repeated beating (e.g. 20-200 times, preferably 20-150 times, more preferably 20-100 times, more preferably 30-50 times) with a syringe.
In another preferred example, the blowing and beating mode is that 210 ml injection syringes are connected with a three-way pipe and repeatedly pushed and beaten at a constant speed.
In another preferred example, in the step (4), the emulsifying is a method of breaking up by a tissue homogenizer.
In another preferred embodiment, in the step (5), before the emulsified fat mixture is processed by centrifugation, the emulsified fat mixture is frozen and then thawed.
In another preferred embodiment, after thawing treatment after freezing, the thawed mixture is used for centrifugation.
In another preferred embodiment, the freezing temperature is from-50 ℃ to-120 ℃, preferably from-60 ℃ to-100 ℃, more preferably from-70 ℃ to-90 ℃.
In another preferred embodiment, the thawing temperature is 20-40 deg.C, preferably 25-40 deg.C, more preferably 37 deg.C.
In another preferred embodiment, the number of cycles of freezing and thawing is 1-5 (preferably 1, 2, 3 or 4).
In another preferred example, in the step (5), after centrifugation, the emulsified fat mixture is layered into 4 layers, the first layer is an oil layer, the second layer is a residual fat tissue layer, the third layer is a liquid layer (i.e. an intermediate liquid layer), and the fourth layer is a cell/tissue debris precipitation layer.
In another preferred embodiment, in the step (5), the centrifugation is performed at 2500 g-.
In another preferred embodiment, in the step (5), the centrifugation time is 1-15min, preferably 1-10min, more preferably 2-8min, and most preferably 3-7 min.
In another preferred embodiment, the temperature of the centrifugation is 2-6 ℃.
In another preferred example, in the step (5), the first layer, the second layer, the third layer and the fourth layer are arranged from top to bottom in sequence.
In another preferred embodiment, in the step (5), the intermediate liquid layer is a transparent or substantially transparent layer.
In another preferred example, in the step (6), the filter bag can remove fat cells in the fat primary extract.
In another preferred embodiment, in the step (6), the filtration and sterilization are performed by a filter (e.g., a 0.22 μm microporous membrane).
In another preferred embodiment, the filter is a microfiltration membrane filter.
In another preferred embodiment, the pore size of the microfiltration membrane is 0.05 to 0.8. mu.m, preferably 0.1 to 0.5. mu.m, more preferably 0.1 to 0.4. mu.m, more preferably 0.15 to 0.3. mu.m, more preferably 0.2 to 0.25. mu.m, most preferably 0.22. mu.m.
In another preferred embodiment, in the step (6), the filtration and sterilization are performed by passing through a first cell-rejecting filter and then a second cell-rejecting filter (e.g., a 0.22 μm filter).
In another preferred example, the step (6) further comprises subpackaging the fat extract to form a subpackaged product. (the sub-packaged extract can be stored at-20 deg.C for use, or thawed at low temperature (such as-4 deg.C) or normal temperature for use directly, or thawed and stored at low temperature (such as 4 deg.C) for a period of time for use).
In a third aspect of the invention, there is provided a cell-free fat extract obtained by the method according to the second aspect of the invention.
In a fourth aspect of the invention, there is provided a composition or formulation comprising (a) a cell-free fat extract according to the third aspect of the invention; and (b) a pharmaceutically, food, nutraceutical, or dietetically acceptable carrier or excipient.
In another preferred embodiment, the composition is a pharmaceutical composition, a food composition, a nutraceutical composition or a dietary supplement.
In another preferred embodiment, the composition or the preparation is in the form of oral preparation, external preparation or injection preparation.
In another preferred embodiment, the composition or the preparation is in the form of powder, granules, capsules, injection, tincture, oral liquid, tablets or buccal tablets.
In another preferred embodiment, the injection is intravenous injection or intramuscular injection.
In another preferred embodiment, the composition or formulation is in the form of a solid dosage form, a semi-solid dosage form, or a liquid dosage form, such as a solution, gel, cream, lotion, ointment, cream, paste, cake, powder, patch, and the like.
In another preferred embodiment, the mass percentage of the cell-free fat extract in the composition or formulation is 5 wt%, preferably 1-20 wt%, based on the total weight of the composition or formulation.
In a fifth aspect of the invention, there is provided a method of preparing a composition or formulation according to the fourth aspect of the invention, said method comprising the steps of: mixing the cell-free fat extract according to the third aspect of the present invention with a pharmaceutically, food, nutraceutical or dietetically acceptable carrier or excipient to form a composition or formulation.
In a sixth aspect of the present invention, there is provided (i) a method for preventing and/or treating erectile dysfunction; and/or (ii) a method of preventing and/or treating cavernous nerve injury of the penis by administering the cell-free fat extract according to the third aspect of the present invention to a subject in need thereof.
In another preferred embodiment, the subject is a human or non-human mammal.
In another preferred embodiment, the non-human mammal includes a rodent, such as a rat, a mouse.
In another preferred embodiment, the administration mode is oral, topical or injection.
In another preferred embodiment, said administration is intracavernosal injection.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows the measurement results of ICP/MAP pressure in rats of each group.
Detailed Description
The present inventors have conducted extensive and intensive studies and have for the first time developed a cell-free fat extract having an excellent therapeutic effect on erectile dysfunction. The research of the embodiment of the invention shows that the cell-free fat extracting solution has excellent improving effect on the injury of the cavernous nerve of the penis and excellent treatment effect on erectile dysfunction caused by the injury of the cavernous nerve of the penis. The present invention has been completed based on this finding.
Term(s) for
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the terms "comprising," "including," and "containing" are used interchangeably and include not only open-ended definitions, but also semi-closed and closed-ended definitions. In other words, the term includes "consisting of … …", "consisting essentially of … …".
In the present invention, the term "prevention" refers to a method of preventing the onset of a disease and/or its attendant symptoms or protecting a subject from acquiring a disease. As used herein, "preventing" also includes delaying the onset of a disease and/or its attendant symptoms and reducing the risk of acquiring a disease in a subject.
"treatment" as used herein includes delaying and stopping the progression of the disease, or eliminating the disease, and does not require 100% inhibition, elimination, or reversal. In some embodiments, the cell-free fat extract of the invention reduces, inhibits, and/or reverses erectile dysfunction, e.g., by at least about 10%, at least about 30%, at least about 50%, or at least about 80%, as compared to an absence of the cell-free fat extract of the invention.
As used herein, the term "IGF-1" is referred to as insulin-like growth factor 1(insulin-like growth factors-1).
As used herein, the term "BDNF" refers to brain-derived neurotrophic factor (BDNF).
As used herein, the term "GDNF" is referred to as glial cell-derived neurotrophic factor (glicellline-derived neurotrophic factor).
As used herein, the term "bFGF" refers to basic fibroblast growth factor (basic fibroblast growth factor).
As used herein, the term "VEGF" is referred to as vascular endothelial growth factor (vascular endothelial growth factor).
As used herein, the term "TGF-. beta.1" refers to transforming growth factor-. beta.1 (transforming growth factor-. beta.1).
As used herein, the term "HGF" refers to hepatocyte growth factor
As used herein, the term "PDGF" refers to Platelet-derived growth factor (Platelet derived growth factor)
As used herein, the term "EGF" refers to Epidermal Growth Factor (Epidermal Growth Factor)
As used herein, the term "NT-3" refers to neurotrophic factor 3 (neurotropphins-3).
As used herein, the term "GH" refers to Growth Hormone (Growth Hormone).
As used herein, the term "G-CSF" refers to a granulocyte colony stimulating factor (granulocytic colony stimulating factor).
Cell free fat extract (CEFFE) and its preparation method
As used herein, the terms "cell-free fat extract of the present invention", "fat extract of the present invention", and the like, which are used interchangeably, refer to an extract (or extract) derived from adipose tissue prepared without the addition of any solution, solvent, small molecule, chemical, and biological additive during the preparation of the fat extract (except for the rinsing step). A typical method of preparing an extract of the invention is as described above in the second aspect of the invention. Furthermore, it is to be understood that while the extract of the present invention does not require the addition of any additives (or additional ingredients) during the preparation process, some or a small amount of a safe substance (such as a small amount of water) that does not adversely or adversely affect the activity of the extract of the present invention may be added.
The acellular fat extract of the invention can be derived from human adipose tissue, is purified from nano-fat by removing oil and cell/extracellular matrix parts after centrifugation, and is a liquid which is acellular, easy to prepare and rich in various growth factors.
In a preferred embodiment of the present invention, the cell-free fat extract is a cell-free fat extract.
The cell-free fat extract according to the present invention may include various cytokines. Typically, the cell-free fat extract comprises one or more of IGF-1, BDNF, GDNF, TGF- β, HGF, bFGF, VEGF, TGF- β 1, PDGF, EGF, NT-3, GH and G-CSF.
In another preferred embodiment, the concentration of IGF-1 in the cell-free fat extract is 5000-30000pg/ml, preferably 6000-20000pg/ml, more preferably 7000-15000pg/ml, more preferably 8000-12000pg/ml, more preferably 9000-11000pg/ml, more preferably 9500-10500 pg/ml.
In another preferred embodiment, the concentration of BDNF in the cell-free fat extract is 800-5000pg/ml, preferably 1000-4000pg/ml, more preferably 1200-2500pg/ml, more preferably 1400-2000pg/ml, more preferably 1600-2000pg/ml, more preferably 1700-1850 pg/ml.
In another preferred embodiment, the concentration of GDNF in the cell-free fat extract is 800-5000pg/ml, preferably 1000-4000pg/ml, more preferably 1200-2500pg/ml, more preferably 1400-2000pg/ml, more preferably 1600-2000pg/ml, more preferably 1700-1900 pg/ml.
In another preferred embodiment, the concentration of bFGF in the cell-free fat extract is 50-600pg/ml, preferably 100-500pg/ml, more preferably 120-400pg/ml, more preferably 150-300pg/ml, more preferably 200-280pg/ml, more preferably 220-260 pg/ml.
In another preferred embodiment, the concentration of VEGF in the cell-free fat extract is 50-500pg/ml, preferably 100-400pg/ml, more preferably 120-300pg/ml, more preferably 150-250pg/ml, more preferably 170-230pg/ml, more preferably 190-210 pg/ml.
In another preferred embodiment, the concentration of TGF-beta 1 in the cell-free fat extract is 200-3000pg/ml, preferably 400-2000pg/ml, more preferably 600-1500pg/ml, more preferably 800-1200pg/ml, more preferably 800-1100pg/ml, more preferably 900-1000 pg/ml.
In another preferred embodiment, the concentration of HGF in the cell-free fat extract is 200-3000pg/ml, preferably 400-2000pg/ml, more preferably 600-1500pg/ml, more preferably 600-1200pg/ml, more preferably 800-1000pg/ml, more preferably 850-950 pg/ml.
In another preferred embodiment, the concentration of PDGF in the cell-free fat extract is 50-600pg/ml, preferably 80-400pg/ml, more preferably 100-300pg/ml, more preferably 140-220pg/ml, more preferably 160-200pg/ml, more preferably 170-190 pg/ml.
In another preferred embodiment, the weight ratio of IGF-1 to VEGF is 20-100: 1, preferably 30-70: 1, more preferably 40 to 60: 1, optimally 45-55: 1.
in another preferred embodiment, the weight ratio of BDNF to VEGF is 2-20: 1, preferably 4-15: 1, more preferably 6 to 12: 1, optimally 8-9.5: 1.
in another preferred embodiment, the weight ratio of GDNF to VEGF is 2-20: 1, preferably 4-15: 1, more preferably 6-12: 1, optimally 8.5-9.5: 1.
in another preferred embodiment, the weight ratio of bFGF to VEGF is 0.2 to 8: 1, preferably 0.5 to 5: 1, more preferably 0.6 to 2: 1, more preferably 0.8 to 1.6: 1, optimally 1-1.5: 1.
in another preferred embodiment, the weight ratio of TGF-beta 1 to VEGF is 1-20: 1, preferably 1 to 15: 1, more preferably 1 to 10: 1, more preferably 2 to 8: 1, more preferably 4 to 6: 1.
in another preferred embodiment, the weight ratio of HGF to VEGF is 1-20: 1, preferably 1 to 15: 1, more preferably 1 to 10: 1, more preferably 2 to 8: 1, more preferably 4 to 5.5: 1.
in another preferred embodiment, the weight ratio of PDGF to VEGF is 0.1 to 3: 1, preferably 0.2-2: 1, more preferably 0.4 to 1.5: 1, optimally 0.7-1.2: 1.
preferably, the cell-free fat extract according to the present invention is prepared by the method according to the second aspect of the present invention as described above.
Typically, the cell-free fat extract according to the present invention is prepared by the following method:
(1) providing an adipose tissue material, disrupting the adipose tissue material, and rinsing (e.g., with physiological saline) to obtain rinsed adipose tissue;
(2) centrifuging the rinsed adipose tissue to obtain a layered mixture;
(3) removing the upper oil layer and the lower water layer from the layered mixture, and collecting the middle layer (i.e., fat layer containing adipocytes);
(4) emulsifying the intermediate layer to obtain an emulsified fat mixture (also called nano-fat);
(5) centrifuging the emulsified fat mixture to obtain an intermediate liquid layer, namely a fat primary extract; and
(6) filtering and sterilizing the fat primary extract to obtain a cell-free fat extract.
In another preferred embodiment, in the step (2), the centrifugation is performed at 2500 g-.
In another preferred embodiment, in the step (2), the centrifugation time is 1-15min, preferably 1-10min, more preferably 1-8min, and most preferably 1-5 min.
In another preferred embodiment, in the step (4), the emulsification is mechanical emulsification.
In another preferred embodiment, the mechanical emulsification is mechanical emulsification by repeated beating (e.g. 20-200 times, preferably 20-150 times, more preferably 20-100 times, more preferably 30-50 times) with a syringe.
In another preferred example, the blowing and beating mode is that 210 ml injection syringes are connected with a three-way pipe and repeatedly pushed and beaten at a constant speed.
In another preferred example, in the step (4), the emulsifying is a method of breaking up by a tissue homogenizer.
In another preferred embodiment, in the step (5), before the emulsified fat mixture is processed by centrifugation, the emulsified fat mixture is frozen and then thawed.
In another preferred embodiment, after thawing treatment after freezing, the thawed mixture is used for centrifugation.
In another preferred embodiment, the freezing temperature is from-50 ℃ to-120 ℃, preferably from-60 ℃ to-100 ℃, more preferably from-70 ℃ to-90 ℃.
In another preferred embodiment, the thawing temperature is 20-40 deg.C, preferably 25-40 deg.C, more preferably 37 deg.C.
In another preferred embodiment, the number of cycles of freezing and thawing is 1-5 (preferably 1, 2, 3 or 4).
In another preferred example, in the step (5), after centrifugation, the emulsified fat mixture is layered into 4 layers, the first layer is an oil layer, the second layer is a residual fat tissue layer, the third layer is a liquid layer (i.e. an intermediate liquid layer), and the fourth layer is a cell/tissue debris precipitation layer.
In another preferred embodiment, in the step (5), the centrifugation is performed at 2500 g-.
In another preferred embodiment, in the step (5), the centrifugation time is 1-15min, preferably 1-10min, more preferably 2-8min, and most preferably 3-7 min.
In another preferred example, in the step (5), the first layer, the second layer, the third layer and the fourth layer are arranged from top to bottom in sequence.
In another preferred embodiment, in the step (5), the intermediate liquid layer is a transparent or substantially transparent layer.
In another preferred example, in the step (6), the filter bag can remove fat cells in the fat primary extract.
In another preferred embodiment, in the step (6), the filtration and sterilization are performed by a filter (e.g., a 0.22 μm microporous membrane).
In another preferred embodiment, the filter is a microfiltration membrane filter.
In another preferred embodiment, the pore size of the microfiltration membrane is 0.05 to 0.8. mu.m, preferably 0.1 to 0.5. mu.m, more preferably 0.1 to 0.4. mu.m, more preferably 0.15 to 0.3. mu.m, more preferably 0.2 to 0.25. mu.m, most preferably 0.22. mu.m.
In another preferred embodiment, in the step (6), the filtration and sterilization are performed by passing through a first cell-rejecting filter and then a second cell-rejecting filter (e.g., a 0.22 μm filter).
In another preferred example, the step (6) further comprises subpackaging the fat extract to form a subpackaged product. (the sub-packaged extract can be stored at-20 deg.C for use, or thawed at low temperature (such as-4 deg.C) or normal temperature for use directly, or thawed and stored at low temperature (such as 4 deg.C) for a period of time for use).
Use of
The present invention provides the use of a cell-free fat extract for the preparation of a composition or formulation for one or more uses selected from the group consisting of: (i) prevention and/or treatment of erectile dysfunction; (ii) preventing and/or treating cavernous nerve injury of penis.
In a preferred embodiment of the invention, the erectile dysfunction is human male erectile dysfunction.
In another preferred embodiment of the present invention, the erectile dysfunction includes erectile dysfunction caused by injury to the cavernous nerve of the penis. The cell-free fat extract of the present invention can prevent and/or treat erectile dysfunction by preventing and/or treating injury of the cavernous nerve of the penis.
Compositions and applications
The compositions of the present invention include (but are not limited to): pharmaceutical compositions, food compositions, health compositions, dietary supplements, and the like.
Typically, the acellular fat extract of the present invention may be prepared into pharmaceutical compositions such as tablets, capsules, powders, fine granules, solutions, troches, jellies, cream formulations, spirits, suspensions, tinctures, poultices, liniments, lotions, and aerosols. The pharmaceutical composition can be prepared by a generally known preparation technique, and a suitable pharmaceutical additive can be added to the drug.
The compositions of the present invention may also include pharmaceutically, comestibly, nutraceutically or dietetically acceptable carriers. "pharmaceutically, food, nutraceutical, or dietetically acceptable carrier" means: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of acceptable carrier parts for pharmaceutically, food, health product or dietary acceptable carrier include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, etc.), calcium sulfate, and calcium sulfatePeanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifierWetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular), topical, preferred modes of administration are oral and injection. For example, the injectable administration is a cavernous penis injection formulation.
The composition or the preparation of the invention is in the form of oral preparation, external preparation or injection preparation. Typically, solid dosage forms for oral administration or administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may comprise opacifying agents.
Liquid dosage forms for oral administration or administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration or administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The cell-free fat extract of the present invention may be administered or dosed alone, or in combination with other drugs for preventing and/or treating fatty liver and/or its complications.
The composition is administered in a safe and effective amount of the cell-free fat extract of the present invention to human or non-human animals (e.g., rats, mice, dogs, cats, cows, chickens, ducks, etc.) in need of treatment, wherein the administration is in an amount that is pharmaceutically, dietetically or nutraceutically acceptable as an effective administration dose. The term "safe and effective amount" as used herein, refers to an amount that produces a function or activity in and is acceptable to humans and/or animals. It will be understood by those skilled in the art that the safe and effective amount may vary with the form of the pharmaceutical composition, the route of administration, the excipients used, the severity of the disease, and the combination with other drugs. For example, for a human having a body weight of 60kg, the daily dose is usually 0.1 to 1000mg, preferably 1 to 600mg, and more preferably 2 to 300 mg. Of course, the particular dosage will also take into account such factors as the route of administration, the health of the patient, and the like, which are within the skill of the skilled practitioner.
The main advantages of the invention include:
1. the invention discovers for the first time that the acellular fat extract has excellent improvement effect on erectile dysfunction and cavernous body nerve injury of the penis, and can be used for treating cavernous body nerve injury type erectile dysfunction of the penis.
2. The cell-free fat extract of the present invention is a cell-free fraction, which can avoid the problems associated with cells in clinical applications, including, for example, genetic stability after cell processing, cell activity and survival rate after injection, multiple administration and storage of cells, and immunogenicity of cells when using allogeneic fats, and has advantages of high safety and low side effects in the preparation of a composition for preventing and treating erectile dysfunction.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1
1. Experimental methods
1.1. Preparation of cell-free fat extract (CEFFE)
Fat was obtained by volunteers under informed consent. The preparation method of the cell-free adipose tissue extract comprises the following steps:
(1) adipose tissue was obtained from 6 healthy women of routine liposuction, mean age 31 years (24-36 years). After local injection of tumescent solution for anesthesia, a 20mL syringe was connected using a 3mm liposuction cannula with a large side hole (2 mm. times.7 mm), and then suction was performed radially under artificial negative pressure to stand the obtained fat still upright, and after removal of tumescent solution, the solution was rinsed 3 times with physiological saline.
(2) The rinsed adipose tissue was placed in a centrifuge tube and centrifuged in a centrifuge at 1200g 4 ℃ for 3 minutes to obtain a layered mixture.
(3) The upper oil layer and the lower aqueous layer were removed from the layered mixture, and the middle layer (i.e., the fat layer containing adipocytes) was collected.
(4) And repeatedly pushing the middle layer for 30 times at constant speed by using 210 ml injection syringes connected with a three-way pipe, so as to perform mechanical emulsification, and obtain a mechanically emulsified fat mixture (also called nano fat).
(5) Placing the mechanically emulsified fat mixture into a refrigerator at minus 80 ℃ for freezing, then carrying out water bath thawing at 37 ℃, after single freeze-thaw cycle, centrifuging the thawed fat mixture for 5 minutes at 1200g and 4 ℃ to obtain a layered mixture, wherein the layered mixture is divided into 4 layers in total, the first layer is an oil layer, the second layer is a residual fat tissue layer, the third layer is a liquid layer, the fourth layer is a cell/tissue fragment sediment layer, removing the oil layer and the residual fat tissue layer, sucking the liquid layer, and avoiding the pollution of the cell/tissue fragment sediment layer in the sucking process, thereby obtaining the primary fat extracting solution.
(6) Filtering the obtained fat primary extract with 0.22 μm filter for sterilization, sterilizing and removing living cells, to obtain cell-free fat extract (CEFFE), freezing at-20 deg.C, and thawing at 4 deg.C.
And detecting the content of cell factors including IGF-1, BDNF, GDNF, bFGF, VEGF, TGF-beta 1, HGF, PDGF and other cell factors by using an ELISA immunoadsorption determination kit for the prepared cell-free fat extracting solution. The average concentration of 6 samples tested was as follows: IGF-1(9840.6pg/ml), BDNF (1764.5pg/ml), GDNF (1831.9pg/ml), bFGF (242.3pg/ml), VEGF (202.9pg/ml), TGF-. beta.1 (954.5pg/ml), HGF (898.4pg/ml) and PDGF (179.9 pg/ml).
1.2 establishment, grouping and administration of cavernous corpus cavernosum nerve-induced erectile dysfunction (CNI-ED) model of rat
Male Sprague-Dawley rats (300-350 g) of 10-12 weeks of age were selected for the experiment, acclimatized in advance for one week, injected intraperitoneally with chloral hydrate, fixed to a temperature-controlled plate in supine position without loss of consciousness. The skin and subcutaneous tissue were dissected along the midline of the abdomen, the bladder was lifted with forceps, the prostate was exposed, and the penile Cavernous Nerve (CN) was carefully isolated at the posterolateral lobe of the prostate. At 5 mm from the greater pelvic nerve (MPG) on both sides, the cavernous nerve of the penis is clamped by a pair of tweezers for 30s and then loosened, the cavernous nerve of the penis is clamped for 30s after 30s, and then the abdominal cavity is closed, so that a rat model of cavernous nerve injury erectile dysfunction (CNI-ED) of the penis is constructed. Sham-operated rats were subjected to direct abdominal closing and skin suturing without any treatment after skin and subcutaneous tissue incision, and the sham-operated rats served as a blank control.
CNI-ED model rats were randomly divided into a model control group, a CEFFE group and an adipose-derived stem cells (ASCs) group, and the rats in each group were administered as follows:
blank control group: 200 mul of physiological saline is locally injected into bilateral corpora cavernosa of SD rats;
model control group: 200 mul of physiological saline is locally injected into bilateral corpora cavernosa of SD rats;
CEFFE group: 200 μ l CEFFE was locally injected to bilateral corpora cavernosa of SD rats;
group of adipose-derived stem cells (ASCs): 200. mu.l of adipose-derived stem cells (1X 10)6Cells/ml) were injected locally into bilateral corpora cavernosa of SD rats.
Groups of CNI-ED rats were observed for restoration of erectile function 4 weeks after administration.
1.3 determination of erectile function
The erectile function of rats was evaluated by recording intracavernous pressure (ICP) using electrical stimulation of the cavernous nerves of the penis. Anesthetizing the rat as before, finding the cavernous nerve of the penis, peeling off and fully exposing the cavernous body of the penis, puncturing a 25G needle into the cavernous body on the left side, and fixing the puncture needle. The left carotid artery was exposed by a median incision in the neck, and the 23G needle was used to puncture the carotid artery and to fix the needle. The method comprises the steps of connecting a needle head connecting a cavernous body of a penis and a carotid artery with a multi-channel physiological recording system through a catheter, filling a heparin solution into the catheter, placing a bipolar electrode to hook a cavernous nerve of the penis, enabling an anode to be located at the proximal end of the nerve, electrically stimulating the cavernous nerve of the penis, simultaneously recording the intracavernosal pressure (ICP) and Mean Arterial Pressure (MAP), stimulating the cavernous nerve of the penis at each side for 3 times, recording the cavernous pressure (ICP) and the Mean Arterial Pressure (MAP), and calculating the ratio (ICP/MAP) of the ICP to the MAP for evaluating the erection function of a rat.
2. Results
The measurement results of ICP/MAP pressure of 4 groups of rats after surgery are shown in figure 1, and it can be seen from figure 1 that the cavernous penis pressure (ICP)/Mean Arterial Pressure (MAP) of the model control group is significantly lower than that of the blank control group, indicating that the cavernous penis nerve injury erectile dysfunction (CNI-ED) model is successfully constructed. ICP/MAP of the CEFFE group and the ASCs group is obviously higher than that of the model control group, and no obvious difference exists between the CEFFE group and the ASCs group, which indicates that both the CEFFE group and the ASCs can obviously improve the penile erection function of CNI-ED.
And (4) conclusion:
the studies in the examples of this application show that CEFFE can improve the erectile function in CNI-ED rats.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. Use of a cell-free fat extract for the preparation of a composition or formulation for one or more uses selected from the group consisting of: (i) prevention and/or treatment of erectile dysfunction; (ii) preventing and/or treating cavernous nerve injury of penis.
2. The use as claimed in claim 1, wherein the erectile dysfunction is male erectile dysfunction.
3. The use of claim 1, wherein the erectile dysfunction comprises erectile dysfunction caused by injury to the cavernous nerve of the penis.
4. The use according to claim 1, wherein the composition or formulation comprises a pharmaceutical composition or formulation, a food composition or formulation, a nutraceutical composition or formulation or a dietary supplement.
5. The use of claim 1, wherein the composition or formulation is in the form of a penile cavernous injection formulation.
6. The use according to claim 1, wherein the cell-free fat extract comprises one or more components selected from the group consisting of: IGF-1, BDNF, GDNF, TGF-beta 1, HGF, bFGF, VEGF, TGF-beta 1, HGF, PDGF, EGF, NT-3, GH, G-CSF, or combinations thereof.
7. The use of claim 6, wherein the cell-free fat extract comprises one or more characteristics selected from the group consisting of:
in the cell-free fat extract, the concentration of IGF-1 is 5000-30000pg/ml, preferably 6000-20000pg/ml, more preferably 7000-15000pg/ml, more preferably 8000-12000pg/ml, more preferably 9000-11000pg/ml, more preferably 9500-10500 pg/ml;
the concentration of BDNF in the cell-free fat extract is 800-5000pg/ml, preferably 1000-4000pg/ml, more preferably 1200-2500pg/ml, more preferably 1400-2000pg/ml, more preferably 1600-2000pg/ml, more preferably 1700-1850 pg/ml;
in the cell-free fat extract, the concentration of GDNF is 800-;
in the cell-free fat extract, the concentration of bFGF is 50-600pg/ml, preferably 100-500pg/ml, more preferably 120-400pg/ml, more preferably 150-300pg/ml, more preferably 200-280pg/ml, more preferably 220-260 pg/ml;
in the cell-free fat extract, the concentration of VEGF is 50-500pg/ml, preferably 100-400pg/ml, more preferably 120-300pg/ml, more preferably 150-250pg/ml, more preferably 170-230pg/ml, more preferably 190-210 pg/ml;
in the cell-free fat extract, the concentration of TGF-beta 1 is 200-3000pg/ml, preferably 400-2000pg/ml, more preferably 600-1500pg/ml, more preferably 800-1200pg/ml, more preferably 800-1100pg/ml, more preferably 900-1000 pg/ml;
in the cell-free fat extract, the concentration of HGF is 200-3000pg/ml, preferably 400-2000pg/ml, more preferably 600-1500pg/ml, more preferably 600-1200pg/ml, more preferably 800-1000pg/ml, more preferably 850-950 pg/ml; and/or
In the cell-free fat extract, the concentration of PDGF is 50-600pg/ml, preferably 80-400pg/ml, more preferably 100-300pg/ml, more preferably 140-220pg/ml, more preferably 160-200pg/ml, more preferably 170-190 pg/ml.
8. The use of claim 6, wherein the cell-free fat extract comprises one or more characteristics selected from the group consisting of:
the weight ratio of IGF-1 to VEGF is 20-100: 1, preferably 30-70: 1, more preferably 40 to 60: 1, optimally 45-55: 1;
the weight ratio of BDNF to VEGF is 2-20: 1, preferably 4-15: 1, more preferably 6 to 12: 1, optimally 8-9.5: 1;
the weight ratio of GDNF to VEGF is 2-20: 1, preferably 4-15: 1, more preferably 6 to 12: 1, optimally 8.5-9.5: 1;
the weight ratio of the bFGF to the VEGF is 0.2-8: 1, preferably 0.5 to 5: 1, more preferably 0.6 to 2: 1, more preferably 0.8 to 1.6: 1, optimally 1-1.5: 1;
the weight ratio of TGF-beta 1 to VEGF is 1-20: 1, preferably 1 to 15: 1, more preferably 1 to 10: 1, more preferably 2 to 8: 1, more preferably 4 to 6: 1;
the weight ratio of HGF to VEGF is 1-20: 1, preferably 1-15: 1, more preferably 1 to 10: 1, more preferably 2 to 8: 1, more preferably 4 to 5.5: 1; and/or
The weight ratio of PDGF to VEGF is 0.1-3: 1, preferably 0.2-2: 1, more preferably 0.4 to 1.5: 1, optimally 0.7-1.2: 1.
9. the use according to claim 1, wherein the cell-free fat extract is prepared by:
(1) providing an adipose tissue material, disrupting the adipose tissue material, and rinsing (e.g., with physiological saline) to obtain rinsed adipose tissue;
(2) centrifuging the rinsed adipose tissue to obtain a layered mixture;
(3) removing the upper oil layer and the lower water layer from the layered mixture, and collecting the middle layer (i.e., fat layer containing fat cells);
(4) emulsifying the intermediate layer to obtain an emulsified fat mixture (also called nano-fat);
(5) centrifuging the emulsified fat mixture to obtain an intermediate liquid layer, namely a fat primary extract; and
(6) filtering and sterilizing the fat primary extract to obtain a cell-free fat extract.
10. A method of (i) preventing and/or treating erectile dysfunction; and/or (ii) a method for preventing and/or treating cavernous nerve injury of the penis, characterized in that a cell-free fat extract is administered to a subject in need thereof.
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CN202011547887.8A CN114668779A (en) | 2020-12-24 | 2020-12-24 | Therapeutic use of acellular fat extracts for erectile dysfunction |
PCT/CN2021/140982 WO2022135545A1 (en) | 2020-12-24 | 2021-12-23 | Use of cell-free fat extract in treatment of erectile dysfunction |
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JP2011051908A (en) * | 2009-08-31 | 2011-03-17 | Univ Of Tokyo | Erectile dysfunction therapeutic composition |
CN105902568A (en) * | 2016-04-29 | 2016-08-31 | 张宁 | Adipose derived stem cell for treating erectile dysfunction |
CN107412264A (en) * | 2017-05-10 | 2017-12-01 | 健生生物技术有限公司 | For treating the medicine and its preparation and application of male erectile disorder |
CN108392493A (en) * | 2018-04-10 | 2018-08-14 | 上海交通大学医学院附属仁济医院 | A kind of injection aquagel and preparation method thereof containing extracellular vesica for treating erectile dysfunction |
CN108498452A (en) * | 2018-04-10 | 2018-09-07 | 上海交通大学医学院附属仁济医院 | A kind of injection aquagel containing stem cell and preparation method thereof for treating erectile dysfunction |
CN110496241A (en) * | 2018-05-16 | 2019-11-26 | 上海交通大学医学院附属第九人民医院 | It is derived from the biomaterial and its preparation method and application of adipose tissue |
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