CN113244171A - Timolol maleate liposome gel and preparation method thereof - Google Patents
Timolol maleate liposome gel and preparation method thereof Download PDFInfo
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- CN113244171A CN113244171A CN202110115360.6A CN202110115360A CN113244171A CN 113244171 A CN113244171 A CN 113244171A CN 202110115360 A CN202110115360 A CN 202110115360A CN 113244171 A CN113244171 A CN 113244171A
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- timolol maleate
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- WLRMANUAADYWEA-NWASOUNVSA-N (S)-timolol maleate Chemical compound OC(=O)\C=C/C(O)=O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 WLRMANUAADYWEA-NWASOUNVSA-N 0.000 title claims abstract description 43
- 239000002502 liposome Substances 0.000 title claims abstract description 43
- 229960005221 timolol maleate Drugs 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 238000001879 gelation Methods 0.000 title description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003906 humectant Substances 0.000 claims abstract description 11
- 239000011159 matrix material Substances 0.000 claims abstract description 9
- 239000003755 preservative agent Substances 0.000 claims abstract description 9
- 230000002335 preservative effect Effects 0.000 claims abstract description 9
- 239000003961 penetration enhancing agent Substances 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 5
- 239000008213 purified water Substances 0.000 claims abstract description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 20
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 15
- SLKDGVPOSSLUAI-PGUFJCEWSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCCCC SLKDGVPOSSLUAI-PGUFJCEWSA-N 0.000 claims description 14
- 239000000463 material Substances 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 11
- 229920002125 Sokalan® Polymers 0.000 claims description 11
- 229960001631 carbomer Drugs 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
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- 150000003904 phospholipids Chemical class 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 239000001856 Ethyl cellulose Substances 0.000 claims description 8
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 8
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 8
- 229920001249 ethyl cellulose Polymers 0.000 claims description 8
- -1 hydroxymethyl ethyl Chemical group 0.000 claims description 8
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- 229920001983 poloxamer Polymers 0.000 claims description 8
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 8
- 238000005303 weighing Methods 0.000 claims description 7
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 claims description 6
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical group OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 claims description 6
- 238000009210 therapy by ultrasound Methods 0.000 claims description 6
- 238000002390 rotary evaporation Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 229960004667 ethyl cellulose Drugs 0.000 claims description 3
- 239000007853 buffer solution Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000003002 pH adjusting agent Substances 0.000 claims description 2
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- 239000002994 raw material Substances 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims 1
- 239000003814 drug Substances 0.000 description 18
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- 208000001969 capillary hemangioma Diseases 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 8
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- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- 206010061619 Deformity Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000542420 Sphyrna tudes Species 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
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Images
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention provides timolol maleate liposome gel and a preparation method thereof, wherein the gel comprises timolol maleate, a penetration enhancer, a humectant, a preservative, a liposome forming agent, a gel matrix, a pH regulator and medical purified water.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to timolol maleate liposome gel and a preparation method thereof.
Background
The infantile hemangioma is a benign tumor frequently occurring in infants, the incidence rate of the infantile hemangioma is 8% -10% in infants, the incidence rate of the infantile hemangioma is up to 22% in premature infants or low-weight newborns, 2/3 occurs in the head and neck, and any part of a body can be affected. Hemangiomas usually proliferate rapidly within 1 year of age and then gradually enter a self-regressive phase for as long as 5-9 years. The hemangioma of infants has high morbidity, and generally has light symptoms and small tumor body, and can be automatically regressed, but the hemangioma of infants has the defects of disfigurement and functional damage caused by the occurrence of special parts such as face, oral cavity, eyes, respiratory tract and the like, and has complications such as ulcer, bleeding and the like in some cases, and even can endanger life, so the hemangioma of infants has to be reasonably treated.
Traditionally, hormone drugs, operations and the like have great side effects when being used for treating infantile hemangioma, and since the treatment effect of oral preparations on infantile hemangioma is obvious, the oral preparations gradually replace treatment means such as hormone and the like, and become first-line drugs for treating infantile hemangioma. The mechanism for treating infantile hemangioma is as follows: promote vasoconstriction in a short term, inhibit a plurality of angiogenesis signal paths in a middle term, and induce endothelial cell apoptosis in a long term, thereby finally causing tumor regression. However, in recent years, studies show that adverse reactions frequently occur, such as wrinkles on superficial skin, diarrhea, milk overflow, irritability, cold limbs and the like during administration.
Therefore, the change of the administration form is a new breakthrough for treating infantile hemangioma. The transdermal drug delivery system can avoid the first pass effect of liver and the inactivation of the drug in gastrointestinal tract, and the absorption of the drug is not influenced by the factors of the gastrointestinal tract. The sustained-release tablet maintains constant effective blood concentration or physiological effect, has long action time, avoids peak valley phenomenon of blood concentration caused by oral administration, reduces toxic and side effects, is convenient to use, and can be independently taken by patients or withdrawn at any time.
The liposome gel has the advantages of smooth appearance, transparency, fineness, proper consistency and viscosity, easy coating and the like, so the externally applied gel prepared from timolol maleate has good research and development values for treating infantile hemangioma.
Although gel preparations are also used, since most of patients are infants under 1 year of age, the requirements for transdermal absorption performance and skin irritation of gel preparations are higher. The penetration enhancer and the timolol maleate are cooperated by a liposome technology to solve the problems of poor transdermal absorption performance and slow release and controlled release of the medicament, so that the medicament concentration of a focus part is always kept at a reasonable action concentration.
Disclosure of Invention
The invention aims to provide timolol maleate liposome gel and a preparation method thereof, and aims to solve the problems in the prior art.
The technical scheme of the invention is as follows:
the timolol maleate liposome gel comprises timolol maleate, a penetration enhancer, a humectant, a preservative, a liposome forming agent, a gel matrix, a pH regulator and medical purified water, wherein the concentration of timolol maleate is 0.1-2%; the penetration enhancer comprises the following materials in parts by weight: 0.05-2.5% azone, 1.0-2.5% propylene glycol, 0.05-1 x10-5% transdermal short peptide; the humectant comprises the following materials in parts by weight: 0.5-5.0% of a humectant; the preservative comprises the following materials in parts by weight: 0.05-0.50% caprylyl hydroximic acid; the liposome forming agent comprises the following materials in parts by weight: 0.5-10% hydrogenated phospholipid dipalmitoyl phosphatidylethanolamine (DPPE), 0.1-2.0% cholesterol; the gel matrix comprises the following materials in parts by weight: 0.1-1.5% of hydroxymethyl ethyl cellulose, 0.2-2.5% of carbomer and 0.1-1.0% of poloxamer P407; the pH regulator comprises the following materials in parts by weight: 0.02-1.20% pH buffer solution.
Further, the humectant is 1, 2, 3-glycerol.
Further, the pH adjusting agent is triethanolamine.
Further, the transdermal short peptide sequence is ACEASLPKHCG.
A method for preparing the timolol maleate liposome gel comprises the following steps:
(1) accurately weighing timolol maleate, hydrogenated phospholipid dipalmitoyl phosphatidylethanolamine (DPPE) and cholesterol, dissolving in an ethanol solution, carrying out rotary evaporation at low temperature under reduced pressure to remove the solvent, forming a layer of uniform film on the wall of a container by phospholipid, adding phosphate buffer solution with pH of 7.4, rotating for 15-45 minutes, standing for 1-3 hours to fully swell and hydrate the cholesterol, and carrying out ultrasonic treatment for 15-45 minutes in ice bath to obtain timolol maleate liposome solution;
(2) taking a clean container, sequentially adding a penetration enhancer, a humectant, hydroxymethyl ethyl cellulose, carbomer and poloxamer P407, heating and stirring to ensure that all the raw materials are dissolved;
(3) and (3) adding the liposome obtained in the step (1) into the mixed solution obtained in the step (2), uniformly stirring, and adding a pH regulator to obtain the timolol maleate liposome gel.
Further, the stirring speed is 100-500 rpm, preferably 350 rpm.
Further, the low temperature is 30-60 ℃, and preferably 45 ℃.
The invention has the advantages that the liposome has bilayer lipid similar to a biological membrane structure, is easy to wrap the medicine, can enable the medicine to quickly permeate the skin and accumulate in the skin, improves the concentration of the medicine at the treatment part, reduces the systemic absorption and reduces the adverse reaction of the medicine. The liposome is mixed with the gel matrix to prepare liposome gel, so that the stability of the liposome can be increased, the applicability of the liposome as an external preparation can be improved, and the slow release and controlled release of the encapsulated drug can be provided.
The timolol maleate liposome gel disclosed by the invention is shown by in vitro drug release, the liposome gel has obvious sustained release and transdermal absorption promotion effects, and compared with the common gel, the accumulated permeation amount and the skin accumulation amount are both obviously improved, so that the liposome gel has more advantages as a drug transdermal absorption carrier compared with the gel.
Drawings
FIG. 1 is a graph of cumulative in vitro permeation.
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like reference numerals refer to the same or similar elements or elements having the same or similar function throughout. The embodiments described below with reference to the accompanying drawings are illustrative only for the purpose of explaining the present invention, and are not to be construed as limiting the present invention.
In the description of the present invention, it is to be understood that the terms "center", "longitudinal", "lateral", "length", "width", "thickness", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", "clockwise", "counterclockwise", and the like, indicate orientations and positional relationships based on those shown in the drawings, and are used only for convenience of description and simplicity of description, and do not indicate or imply that the device or element being referred to must have a particular orientation, be constructed and operated in a particular orientation, and thus, should not be considered as limiting the present invention. Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, features defined as "first", "second", may explicitly or implicitly include one or more of the described features. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
In the description of the present invention, it should be noted that, unless otherwise explicitly specified or limited, the terms "mounted," "connected," and "connected" are to be construed broadly, e.g., as meaning either a fixed connection, a removable connection, or an integral connection; may be mechanically connected, may be electrically connected or may be in communication with each other; either directly or indirectly through intervening media, either internally or in any other relationship. The specific meanings of the above terms in the present invention can be understood by those skilled in the art according to specific situations.
In the present invention, unless otherwise expressly stated or limited, "above" or "below" a first feature means that the first and second features are in direct contact, or that the first and second features are not in direct contact but are in contact with each other via another feature therebetween. Also, the first feature being "on," "above" and "over" the second feature includes the first feature being directly on and obliquely above the second feature, or merely indicating that the first feature is at a higher level than the second feature. A first feature being "under," "below," and "beneath" a second feature includes the first feature being directly under and obliquely below the second feature, or simply meaning that the first feature is at a lesser elevation than the second feature.
The following disclosure provides many different embodiments or examples for implementing different features of the invention. To simplify the disclosure of the present invention, the components and arrangements of specific examples are described below. Of course, they are merely examples and are not intended to limit the present invention. Furthermore, the present invention may repeat reference numerals and/or letters in the various examples, such repetition is for the purpose of simplicity and clarity and does not in itself dictate a relationship between the various embodiments and/or configurations discussed. In addition, the present invention provides examples of various specific processes and materials, but one of ordinary skill in the art may recognize applications of other processes and/or uses of other materials.
Example 1
The component ratio is as follows: 0.5% of timolol maleate, 1.0% of azone, 1x 10-5% of transdermal short peptide, 1.0% of propylene glycol, 2.0% of DPPE, 0.25% of cholesterol, 2.5% of glycerol, 0.5% of hydroxymethyl ethyl cellulose, 0.15% of carbomer, poloxamer P4070.5%, 0.1% of caprylyl hydroximic acid, 0.125% of triethanolamine, and the balance of water
The preparation method comprises the following steps:
1. accurately weighing 0.5g of timolol maleate, 2.0g of hydrogenated phospholipid dipalmitoyl phosphatidylethanolamine (DPPE) and 0.5g of cholesterol in a pear-shaped bottle, adding 50mL of ethanol to dissolve the timolol maleate, performing ultrasonic treatment for 10 minutes, performing reduced pressure rotary evaporation at 45 ℃ to remove the ethanol solvent to form a uniform thin film on the wall of the container, adding 20mL of PBS (pH7.4PBS), rotating for 30 minutes, standing for 2 hours to fully hydrate the phospholipid, and performing ultrasonic treatment for 25 minutes under ice bath conditions to obtain timolol maleate liposome solution; 3 batches of samples were prepared and the average encapsulation efficiency was found to be 85.32%.
2. Precisely weighing azone 1.0g and transdermal short peptide 1x10-5g. 1.0g of propylene glycol and 0.1g of caprylyl hydroximic acid are placed in a beaker, and a proper amount of water is added and stirred evenly to obtain the preservative osmotic solution.
3. 2.5g of glycerol, 0.5g of hydroxymethyl ethyl cellulose, 0.15g of carbomer and 70.5 g of poloxamer P4070 are precisely weighed and placed in a beaker, evenly mixed, added with proper amount of water and evenly stirred to ensure that the carbomer is fully dispersed and swelled for 4 hours, gradually added with 0.125g of triethanolamine and placed in a gel matrix, and stirred to form gel. And mixing the encapsulated timolol maleate liposome and the preservative osmotic solution into the gel, uniformly stirring at 250rpm for 10 minutes, and finally preparing the timolol maleate liposome gel.
Example 2
The component ratio is as follows: 0.5% of timolol maleate, 0.5% of azone, 5x 10-5% of transdermal short peptide, 2.0% of propylene glycol, 4.0% of DPPE, 0.45% of cholesterol, 4.5% of glycerol, 0.35% of hydroxymethyl ethyl cellulose, 0.25% of carbomer, poloxamer P4070.25%, 0.1% of caprylyl hydroximic acid, 0.25% of triethanolamine, and the balance of water
The preparation method comprises the following steps:
1. accurately weighing 0.5g of timolol maleate, 4.0g of hydrogenated phospholipid dipalmitoyl phosphatidylethanolamine (DPPE) and 0.45g of cholesterol in a pear-shaped bottle, adding 50mL of ethanol to dissolve the timolol maleate, performing ultrasonic treatment for 10 minutes, performing reduced pressure rotary evaporation at 40 ℃ to remove the ethanol solvent to form a uniform thin film on the wall of the container, adding 20mL of PBS (pH7.4PBS), rotating for 30 minutes, standing for 2 hours to fully hydrate the phospholipid, and performing ultrasonic treatment for 30 minutes under an ice bath condition to obtain timolol maleate liposome solution; 3 batches of samples were prepared and the average encapsulation efficiency was found to be 82.75%.
2. Accurately weighing azone 0.5g and transdermal short peptide 5x10-5g. 2.0g of propylene glycol and 0.1g of caprylyl hydroximic acid are placed in a beaker, and a proper amount of water is added and stirred evenly to obtain the preservative osmotic solution.
3. Precisely weighing 4.5g of glycerol, 0.35g of hydroxymethyl ethyl cellulose, 0.25g of carbomer and 70.25g of poloxamer P4070, uniformly mixing, adding a proper amount of water, uniformly stirring to fully disperse the carbomer, swelling for 6 hours, gradually adding 0.25g of triethanolamine into a gel matrix, and stirring to form gel. And mixing the encapsulated timolol maleate liposome and the preservative osmotic solution into the gel, uniformly stirring at 250rpm for 15 minutes, and finally preparing the timolol maleate liposome gel.
In vitro transdermal permeation kinetics study of timolol maleate liposome gel:
healthy male white rats were anesthetized, immediately after which the rat hair on the abdominal skin was carefully cut off with a pet trimmer, and after the short hair was removed with a razor, the rats were sacrificed and the abdominal skin was peeled off. Spreading the peeled skin on a smooth plate with stratum corneum facing downwards, removing subcutaneous fat and adhesive with small eye scissors, repeatedly washing with normal saline, cutting into appropriate size, checking skin integrity, placing in a sealed plastic bag, and storing in refrigerator. The integrity of the rat skin was checked visually before the experiment without any breakage.
The whole skin of the abdomen of the treated rat was removed and fixed to the modified Franz diffusion cell with the stratum corneum facing the feeding chamber. Adding 3g of gel into a supply chamber, filling a receiving chamber with receiving medium (pH7.4PBS, effective volume of 8ml), preserving heat of the whole experimental system by using a 37 +/-0.5 interlayer circulating water bath, sampling from the receiving chamber within 1, 2, 4, 6, 8, 10 and 12 hours respectively, simultaneously supplementing the receiving chamber with equal amount of isothermal receiving medium, filtering the sample by using a 0.45um microporous filter membrane, appropriately diluting, accurately measuring 10ul of timolol maleate reference substance solution for sample injection by using a peak area measurement, and measuring the peak area at a 247nm wavelength. Calculating the concentration of timolol in a receiving medium by using the peak area according to an external standard method, respectively calculating the cumulative permeation quantity Qt of the medicament at different time, and performing linear regression on the linear part of a curve of Qt to time t, wherein the slope of the linear is the percutaneous permeation rate J (ug cm-2 h-1). A1% carbomer matrix was selected as a comparison subject and subjected to a t-test using Excel software. The cumulative permeation Q is calculated as:
where Cn is the drug concentration measured at the nth sampling, CS is the drug concentration measured at the first to (n-1) th sampling, VR is the volume of receiving medium initially charged to the receiving chamber, and VS is the sampling volume.
TABLE 1 in vitro cumulative permeation
Referring to fig. 1 and table 1, in vitro drug release results show that timolol maleate liposome gel has obvious sustained release and transdermal absorption promoting effects, and compared with timolol maleate gel, the cumulative permeation amount and skin accumulation amount are both significantly improved, which indicates that liposome gel is more advantageous as a drug transdermal absorption carrier compared with gel.
While the preferred embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that the invention is not limited thereto, and that various changes and modifications may be made without departing from the spirit of the invention, and the scope of the appended claims is to be accorded the full scope of the invention.
Claims (7)
1. The timolol maleate liposome gel is characterized by comprising timolol maleate, a penetration enhancer, a humectant, a preservative, a liposome forming agent, a gel matrix, a pH regulator and medical purified water, wherein the concentration of timolol maleate is 0.1-2%; the penetration enhancer comprises the following materials in parts by weight: 0.05-2.5% azone, 1.0-2.5% propylene glycol, 0.05-1 x10-5% transdermal short peptide; the humectant comprises the following materials in parts by weight: 0.5-5.0% of a humectant; the preservative comprises the following materials in parts by weight: 0.05-0.50% caprylyl hydroximic acid; the liposome forming agent comprises the following materials in parts by weight: 0.5-10% hydrogenated phospholipid dipalmitoyl phosphatidylethanolamine (DPPE), 0.1-2.0% cholesterol; the gel matrix comprises the following materials in parts by weight:0.1-1.5% of hydroxymethyl ethyl cellulose, 0.2-2.5% of carbomer and 0.1-1.0% of poloxamer P407; the pH regulator comprises the following materials in parts by weight: 0.02-1.20% pH buffer solution.
2. The timolol maleate liposome gel of claim 1, wherein the humectant is 1, 2, 3-propanetriol.
3. The timolol maleate liposome gel of claim 1, wherein the pH adjusting agent is triethanolamine.
4. The timolol maleate liposome gel of claim 1, wherein the transdermal short peptide sequence is ACEASLPKHCG.
5. A method of preparing the timolol maleate liposome gel of claim 1 comprising the steps of:
(1) accurately weighing timolol maleate, hydrogenated phospholipid dipalmitoyl phosphatidylethanolamine (DPPE) and cholesterol, dissolving in an ethanol solution, carrying out rotary evaporation at low temperature under reduced pressure to remove the solvent, forming a layer of uniform film on the wall of a container by phospholipid, adding phosphate buffer solution with pH of 7.4, rotating for 15-45 minutes, standing for 1-3 hours to fully swell and hydrate the cholesterol, and carrying out ultrasonic treatment for 15-45 minutes in ice bath to obtain timolol maleate liposome solution;
(2) taking a clean container, sequentially adding a penetration enhancer, a humectant, hydroxymethyl ethyl cellulose, carbomer and poloxamer P407, heating and stirring to ensure that all the raw materials are dissolved;
(3) and (3) adding the liposome obtained in the step (1) into the mixed solution obtained in the step (2), uniformly stirring, and adding a pH regulator to obtain the timolol maleate liposome gel.
6. The method for preparing timolol maleate liposome gel according to claim 5, wherein the stirring speed is 100-500 rpm.
7. The method of claim 5, wherein the low temperature is 30-60 ℃.
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