CN114010620A - Composition mucosa preparation for relieving muscae volitantes, and preparation method and application thereof - Google Patents
Composition mucosa preparation for relieving muscae volitantes, and preparation method and application thereof Download PDFInfo
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- CN114010620A CN114010620A CN202111179439.1A CN202111179439A CN114010620A CN 114010620 A CN114010620 A CN 114010620A CN 202111179439 A CN202111179439 A CN 202111179439A CN 114010620 A CN114010620 A CN 114010620A
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- notoginsenoside
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- nicotinamide mononucleotide
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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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses a notoginsenoside and nicotinamide mononucleotide composite external transdermal absorbent and a preparation method thereof, belonging to the technical field of medicinal preparations. The notoginsenoside and nicotinamide mononucleotide composite transdermal absorbent for external use is obtained by adding notoginsenoside molecular microcapsules into a blank matrix by an equivalent gradual adding method to uniformly disperse the notoginsenoside molecular microcapsules, then adding corresponding nicotinamide mononucleotide according to a proportion, adding a humectant, an emulsifier and a penetration enhancer, uniformly stirring, adding a pH regulator, and regulating the pH value to 6-7. The compound external transdermal absorbent containing the notoginsenoside and the nicotinamide mononucleotide provided by the invention has strong curative effect of compound medication, can avoid the defects of low bioavailability, strong irritation and the like brought by the existing medicine, has the characteristics of good absorptivity, strong stability, no irritation and the like, overcomes the defect that the notoginsenoside is difficult to be absorbed through skin due to large molecular weight, and realizes the purpose of externally treating the muscae volitantes by the notoginsenoside.
Description
Technical Field
The invention belongs to the field of medical treatment and health, particularly relates to a composition for relieving muscae volitantes, a preparation and application thereof, and particularly relates to a composition which has the effects of promoting blood circulation to remove blood stasis and is compounded by using notoginsenoside and nicotinamide mononucleotide so as to reduce the lipidization shape of eyeground blood vessels, thereby fundamentally solving the problem of muscae volitantes caused by viscosity of blood fat. The preparation formed by the composition has the characteristics of simple preparation method and safe and convenient use.
Background
The muscae volitantes is a disease characterized clinically by the black shadow floating in front of eyes accompanied by hypopsia. The muscae volitantes is a common disease of ophthalmology, and the incidence of muscae volitantes is mostly the middle-aged and old people over 40 years old. With the development of society and the acceleration of life rhythm, the living pressure of people is continuously increased, and liver depression, qi stagnation and blood stasis are easy to occur due to emotional discomfort. Meanwhile, modern people mostly like to eat fried and fat, sweet and thick greasy food, which is easy to increase the blood fat content. In addition, electronic products such as mobile phones and computers are preferred for long-term vision, blood loss due to long-term vision, impairment of spirit after staying up all night, blood stored in the liver, and insufficient blood, which can not nourish eyes. So the modern mosquito disease patients are increasing day by day.
At present, the commonly used medicines for treating the muscae volitantes on the market mainly comprise amiodarone eye drops. The amiodarone eye drops are easy to cause allergic reactions of conjunctival congestion, eyelid congestion, pruritus and the like of a patient after being used for a long time. And the eyeball tissues have a plurality of physiological barriers, which obstruct the effective transmission of the therapeutic drugs, resulting in the reduction of the drug absorption amount and the low bioavailability of the eye drops. According to the characteristics that the skin thickness of human eyelid is only 0.9nm and the penetration pressure around eyes is high in the acceptance degree of the external preparation. Can be used for preparing an external transdermal absorption preparation which has no irritation and is convenient to use, improving the treatment effect and reducing the adverse reaction brought by the existing medicines.
In the ancient prescription, Yu Qi Yao Jie (medicine solution for Jade Soy) records that the pseudo-ginseng regulates nutrient and stops bleeding, promotes blood circulation and removes blood stasis, and removes blood stasis to astringe new blood. The Chinese herbal medicine records: pseudo-ginseng, the old and the young know only the efficacy of stopping bleeding and stopping pain, especially the pain caused by blood stasis, and the blood caused by spreading and dispersing, and the pseudo-ginseng has bitter and warm flavor and can enter the blood to differentiate the blood stasis. On the basis, the modern medicine deepens the research on the pseudo-ginseng. The data show that the panax notoginseng saponins can also inhibit lipid synthesis, promote lipid transportation and removal, accelerate lipid excretion and adjust blood fat by reducing the absorption of exogenous lipid. Youngson N A et al studied that Nicotinamide Mononucleotide (NMN) reduces lipid levels in blood vessels, and ameliorates vascular dysfunction and increases arterial elastin accumulation.
Therefore, the notoginsenoside and nicotinamide mononucleotide are compounded for use, so that the lipidization symptom of the fundus blood vessels can be relieved, the blood microcirculation is improved, and the muscae volitantes caused by the viscosity of blood fat is fundamentally solved. But notoginsenoside has poor water solubility and large molecular weight and has low transdermal absorption rate when directly used externally. Meanwhile, when the notoginsenoside and the nicotinamide mononucleotide are used in a compounding way, the technical difficulty of the transdermal absorption preparation caused by the effective concentration of the notoginsenoside and the nicotinamide mononucleotide entering blood circulation becomes a restriction bottleneck. It is therefore important to find an external preparation that can alleviate muscae volitantes during sleep at an effective drug concentration.
Disclosure of Invention
The invention aims to solve the problem of muscae volitantes caused by fundus blood vessel lipidization, and provides a mucosal preparation which has a night lasting period of 6-8 h and releases a notoginsenoside microcapsule and nicotinamide mononucleotide compound according to a certain rule and a preparation method thereof.
The invention provides a compound mucosa preparation of notoginsenoside liposome and nicotinamide mononucleotide, which comprises a mucosa gel and notoginsenoside liposome and nicotinamide mononucleotide dispersed in the gel, wherein the liposome microcapsule takes soybean lecithin and cholesterol as capsule wall materials and notoginsenoside as an active ingredient.
As an improvement of the technical scheme, the matrix is a mixture of sodium polyacrylate, polyvinylpyrrolidone and gelatin.
The invention also provides a preparation method of the composition mucosa preparation for relieving the muscae volitantes, which comprises the following process steps:
(1) uniformly mixing water-soluble high polymer material sodium polyacrylate, polyvinylpyrrolidone, gelatin and deionized water to obtain blank eye gel;
(2) uniformly mixing soybean lecithin, cholesterol and trichloromethane to prepare a capsule wall material;
(3) dissolving notoginsenoside in phosphate buffer solution to obtain phosphate buffer solution of notoginsenoside
(4) Dropwise adding the notoginsenoside phosphate buffer solution obtained in the step (3) into the capsule wall material obtained in the step (2) to form a uniform mixture, freezing and centrifuging at 4 ℃, removing supernatant, collecting precipitate, and freeze-drying to obtain notoginsenoside molecular microcapsules;
(5) the liposome microcapsules were dispersed into the gel in equal increments.
(6) And (3) adding nicotinamide mononucleotide to the gel (5) in proportion and mixing uniformly.
(7) And (3) uniformly coating the membrane base film (6) to the thickness of 1-10 um, cutting the membrane base film to form a crescent shape suitable for the lower eyelid part of the eyes, and covering a CPP membrane for isolation and packaging by using EW9100 non-woven fabric as a backing.
On the basis of the scheme, the ratio of the notoginsenoside to the nicotinamide mononucleotide is 1: 1-3.
On the basis of the scheme, the gel contains 3-6% of sodium polyacrylate.
On the basis of the scheme, the phospholipid ratio of the microcapsule is 1: 6 to 10.
On the basis of the scheme, the medicine-lipid ratio of the notoginsenoside microcapsules is 1: 2 to 10.
On the basis of the scheme, the particle size of the notoginsenoside liposome microcapsule is 200-300 nm.
On the basis of the scheme, the blank matrix is prepared by heating, swelling and uniformly mixing sodium polyacrylate and polyvinylpyrrolidone, wherein the mass ratio of the polyvinylpyrrolidone to the sodium polyacrylate is 1:1 to 3.
On the basis of the scheme, the humectant is glycerin.
On the basis of the scheme, the cross-linking agent is aluminum hydroxide.
On the basis of the scheme, the filler is zinc oxide.
Based on the scheme, the transdermal absorption enhancer is azone.
On the basis of the scheme, the mass ratio of the compound medicine to the blank matrix is 1: 10 to 30.
On the basis of the scheme, the mass-to-volume ratio (w/v) of the compound medicine to the humectant is 1: 2-4 (w/v).
On the basis of the scheme, the mass ratio of the compound medicine to the cross-linking agent is (w/w) 1:1 to 1.25 (w/w).
On the basis of the scheme, the mass ratio (w/w) of the compound medicine to the transdermal absorption enhancer is 1:1 to 1.55 (w/w).
In the invention, the sodium polyacrylate is a water-soluble high polymer material which can be crosslinked with high-valence metal ions to form a crosslinked network structure, so that the cohesive strength of the matrix is improved, and the film sticking agent is prevented from falling off, thereby solving the problems of film sticking agent residue, clothes pollution and the like.
The invention also discloses a notoginsenoside microcapsule and nicotinamide mononucleotide composite external patch, which is prepared by uniformly coating the notoginsenoside microcapsule and nicotinamide mononucleotide composite external transdermal absorbent on a backing layer with the thickness of 0.5-1mm, then covering a polyester protective film subjected to anti-sticking treatment on the notoginsenoside microcapsule and nicotinamide mononucleotide composite external transdermal absorbent, and blanking, screening, quality inspection and packaging according to specifications after sterilization.
The invention has the beneficial effects that:
compared with the existing drugs for treating muscae volitantes in the market, the invention adopts the notoginsenoside liposome and nicotinamide mononucleotide to mix to prepare the gel composite system, the drug has obvious release rule, and the effective period basically covers one sleep cycle for 6-8 h.
The gel complex is beneficial to ensuring the clinical application safety of the notoginsenoside, is different from oral or intravenous injection and other systemic medicines for local external application, is easily accepted by patients, and improves the treatment compliance of the patients.
The skin permeability and bioavailability of the invention are greatly improved; the preparation process is simple, can be used for industrial production, and has obvious therapeutic significance.
Drawings
FIG. 1 is the drug release curve of the compound transdermal absorbent for external use of notoginsenoside and nicotinamide mononucleotide;
FIG. 2 is a drug release profile of three batches of trial products of the pseudo-ginseng saponin and nicotinamide mononucleotide composite topical transdermal absorbent;
Detailed Description
Terms used in the present invention have generally meanings as commonly understood by one of ordinary skill in the art, unless otherwise specified.
The present invention will be described in further detail with reference to the following data in conjunction with specific examples. The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
Example 1 preparation of notoginsenoside microcapsules and Nicotinamide mononucleotide composite transdermal absorbent for external use
1. Process for preparing notoginsenoside microcapsule and nicotinamide mononucleotide composite external transdermal absorbent
(1) Preparation of notoginsenoside molecular microcapsule
Prescription: notoginsenoside: soybean lecithin: cholesterol (w/w) ═ 2:8:1
The preparation method comprises the following steps:
25mg of notoginsenoside powder was dissolved in 5ml of phosphate buffer (pH6.8) to prepare an aqueous phase. Dissolving 100mg soybean lecithin and 12.5mg cholesterol in 40ml chloroform to dissolve completely, transferring to a rotary evaporator, rotary evaporating at 25 deg.C to remove organic solvent, controlling the rotation speed of the rotary evaporator to form a uniform thin film on the wall of the round bottom flask, drying for 24 hr, adding buffer solution containing notoginsenoside, rotary washing at 25 deg.C for 150min to obtain viscous suspension, freeze-centrifuging at 4 deg.C, removing supernatant, collecting precipitate, and freeze-drying to obtain notoginsenoside microcapsule.
(2) Preparation of blank matrix
Prescription: 0.456g of sodium polyacrylate, 0.395g of polyvinylpyrrolidone, 0.08g of aluminum hydroxide, 1.5g of glycerol, 0.4g of carbomer, 0.02g of tartaric acid and 0.12g of azone.
Dissolving sodium polyacrylate in glycerol, mixing polyvinylpyrrolidone and carbomer uniformly, and adding into water for swelling; adding zinc oxide, aluminum hydroxide, tartaric acid and azone, dissolving in a small amount of water, mixing uniformly in water bath at 60 deg.C, and coating.
(3) Preparation of notoginsenoside microcapsule and nicotinamide mononucleotide composite external transdermal absorbent
And (3) dispersing 1.86g of the compound medicine into the blank matrix prepared in the step (2) according to an equivalent gradual addition method to obtain the notoginsenoside microcapsule and nicotinamide mononucleotide compound external transdermal absorbent.
2. Drug release detection of notoginsenoside microcapsule and nicotinamide mononucleotide composite external transdermal absorbent
Aiming at the treatment of the ocular vascular occlusion diseases, the blood flow of the ocular blood vessels, the oral administration of the panax notoginseng saponins and the nicotinamide mononucleotide and the average drug absorption amount are combined. The interception flow of the dialysis bag is used as simulation data of absorption through skin to judge the transmittance of the prepared molecular microcapsule, and the in-vivo drug release and absorption behavior rule of the notoginsenoside and nicotinamide mononucleotide molecular microcapsule in vitro simulation can be effectively judged. The dialysis bag structure is made of regenerated cellulose, and the permeation radius conforms to the skin simulation radius.
A dialysis method is adopted to simulate the process that notoginsenoside and nicotinamide mononucleotide in an external transdermal absorbent are absorbed and enter blood circulation after being released in vivo, and the steps are as follows:
placing 5mL of compound topical transdermal absorbent containing notoginsenoside and nicotinamide mononucleotide in dialysis bag (interception 14000D, regenerated cellulose membrane), soaking in dissolution medium containing 100mL of physiological saline, maintaining constant temperature at 35 + -0.5 deg.C, respectively taking 5mL of dialysate at 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, and 48h, simultaneously supplementing equivalent physiological saline, maintaining medium volume, measuring compound drug content in sample at 268nm by ultraviolet spectrophotometry, and determining content of compound drug according to formula
(Cn is the concentration of the drug at the sampling time of the nth time, Vn is the volume of the dissolution medium, Ci is the concentration of the drug at the sampling time of the ith time, and Vi is the volume of the sample), the cumulative release rate is calculated, and an in vitro release curve is drawn, so that the release amount of the notoginsenoside and nicotinamide mononucleotide composite absorbent at each time period is obtained, as shown in figure 1. From fig. 1, the drug release of the notoginsenoside and nicotinamide mononucleotide composite external transdermal absorbent has the equation of Q ═ 84.75552 (1-e)-0.1858t) Wherein Q represents the cumulative drug release rate (%), t represents the time (h), e is a natural constant, and the fitting coefficient R2＝0.9898>0.9, the release of the complex system in physiological saline conforms to the first order kinetics law, that is, the drug is released by diffusion.
Example 2 preparation of a Pilot product (three batches) of a notoginsenoside microcapsule and nicotinamide mononucleotide composite transdermal absorption agent for external use
Three batches of the pseudo-ginseng saponin micro-capsules and nicotinamide mononucleotide composite external transdermal absorbent pilot products 100 parts per batch are prepared according to the formula in the table 2 in the method of the example 1 (1).
TABLE 1
The release determination method of the compound drugs in the three batches of external transdermal absorbent pilot products is the same as that in examples 1-2, the detection results are shown in table 2, and fig. 2 shows the release rule of the compound drugs.
TABLE 2
As shown in figure 1, the notoginsenoside microcapsule and nicotinamide mononucleotide composite topical transdermal absorbent can rapidly reach effective dose in physiological saline, has lasting action for 6-8 hours, can be used for treating during sleep time, and does not affect normal work and life of patients
The above embodiments are intended to illustrate that the present invention may be implemented or used by those skilled in the art, and therefore the present invention includes, but is not limited to, the above embodiments, any methods, processes, products, etc., which are consistent with the principles and novel and inventive features disclosed herein, and which are within the scope of the present invention.
Claims (10)
1. The composition for relieving muscae volitantes, the preparation and the application thereof are characterized in that the composition for relieving muscae volitantes is notoginsenoside and nicotinamide mononucleotide, the preparation is in the form of a patch, and the use method is that the composition is used for sleeping at night for 6-10 hours per time.
2. The composition of claim 1, wherein the composition comprises notoginsenoside and nicotinamide mononucleotide in a mass ratio (w/w) of 1: 1-3. The auxiliary materials of the preparation formed by the composition are sodium polyacrylate, polyvinylpyrrolidone, gelatin, aluminum hydroxide, glycerol, carbomer, tartaric acid and azone.
3. The compound preparation of notoginsenoside and nicotinamide mononucleotide as claimed in claim 2, wherein the mass ratio (w/w) of total auxiliary materials to medicine is 15-30: 1-6.
4. The preparation method according to claim 3, wherein the optimal blank gel is prepared by dissolving sodium polyacrylate in glycerol, mixing polyvinylpyrrolidone and carbomer uniformly, adding into water, and swelling; adding zinc oxide, aluminum hydroxide, tartaric acid and azone, dissolving in a small amount of water, and mixing uniformly in water bath at 60 deg.C.
5. The preparation method of the composition preparation for relieving the muscae volitantes is characterized by comprising the following process steps of:
(1) a blank gel suitable for the fundus is prepared.
(2) Making quantitative notoginsenoside into microcapsule, dissolving in ethanol, adding blank gel, and mixing.
(3) Adding nicotinamide mononucleotide to the gel of 3(2) and mixing.
(4) And (3) uniformly coating the film bottom with the thickness of 1-10 um, cutting the film bottom to form a crescent shape suitable for the lower eyelid part of the eye, and covering a CPP film by using EW9100 non-woven fabric as a backing for isolation and packaging.
6. The microcapsule prepared by the preparation method according to claim 5, wherein the notoginsenoside is dissolved in a buffer to form an aqueous phase; dissolving phospholipid capsule wall material in organic solvent to form oil phase; and (3) performing rotary evaporation on the oil phase to form a uniform film, adding the water phase, continuously hydrating for a period of time to form a microcapsule suspension, performing ultrasonic dispersion under an ice bath condition, performing refrigerated centrifugation at 4 ℃, removing supernatant, collecting precipitate, and performing freeze drying to obtain the notoginsenoside molecular microcapsule.
7. The method according to claim 6, wherein the organic solvent is chloroform, and the buffer solution is a phosphate buffer solution (pH 6.8).
8. The method according to claim 6, wherein the mass ratio of lecithin to cholesterol is 1: 6 to 10.
9. The preparation method according to claim 6, wherein the mass ratio of the notoginsenoside to the lecithin is 1: 2 to 10.
10. A patch for external use for treating muscae volitantes is characterized by comprising a protective layer, a backing layer, a viscose layer and a reservoir layer, wherein the reservoir layer is a composite preparation of notoginsenoside and nicotinamide mononucleotide in claims 1-6.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202111179439.1A CN114010620A (en) | 2021-10-11 | 2021-10-11 | Composition mucosa preparation for relieving muscae volitantes, and preparation method and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202111179439.1A CN114010620A (en) | 2021-10-11 | 2021-10-11 | Composition mucosa preparation for relieving muscae volitantes, and preparation method and application thereof |
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