CN106361728B - Percutaneous absorption preparation and method for producing percutaneous absorption preparation - Google Patents
Percutaneous absorption preparation and method for producing percutaneous absorption preparation Download PDFInfo
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- CN106361728B CN106361728B CN201610574331.5A CN201610574331A CN106361728B CN 106361728 B CN106361728 B CN 106361728B CN 201610574331 A CN201610574331 A CN 201610574331A CN 106361728 B CN106361728 B CN 106361728B
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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
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
Abstract
The invention discloses a percutaneous absorption preparation containing oseltamivir or pharmaceutically acceptable salts thereof, which comprises the following components in part by weight: a backing layer; a protective layer; and a pharmaceutical preparation layer located between the backing layer and the protective layer, wherein the pharmaceutical preparation layer contains oseltamivir or a pharmaceutically acceptable salt thereof. The percutaneous absorption preparation avoids adverse reaction of a digestive system caused by oral administration; meanwhile, the transdermal absorption preparation is convenient to administer and can improve the compliance of patients. In addition, the method for preparing the percutaneous absorption preparation disclosed by the invention is simple, convenient and cheap, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals. In particular, the present invention relates to a transdermal absorption preparation and a method for preparing the transdermal absorption preparation.
Background
Oseltamivir, chemical name is (3R,4R,5S) -4-acetamido-5-amino-3- (1-ethyl propoxy) cyclohexene-1-carboxylic acid ethyl ester. The chemical structural formula is as follows:
oseltamivir has strong neuraminidase inhibition activity, is effective to A, B influenza viruses, and information such as properties and a preparation method thereof is disclosed in WO 1998007685A 1 and WO 1996026933A 1.
The oseltamivir is available on the market at present in the dosage forms of granules, capsules, dry suspensions and the like. However, oseltamivir is a drug having a particularly large bitter taste, and thus its pharmaceutical composition for oral administration is difficult to swallow. In the prior art, the bitter taste of oseltamivir is usually masked by adding a sweetener to the composition or in the form of a capsule formulation.
Chinese patent CN 101389323B discloses a pharmaceutical composition comprising an excipient and oseltamivir phosphate, wherein the excipient is selected from one or more of sugars and sugar alcohols having an equilibrium moisture content of 1 wt% or less at 25 ℃ and a relative humidity of 70%, and the contents of glucose and mannose contained in the sugars and sugar alcohols are 0.01 wt% or less, respectively. In order to suppress the bitter taste of the pharmaceutical composition, a high sweetener (such as sucrose or steviosin) is also added to the invention to mask the bitter taste.
Chinese patent CN 1820774B discloses oseltamivir phosphate granules and a preparation method thereof, wherein the granules comprise 1.97-19.8 wt% of oseltamivir phosphate, 75.0-97.5 wt% of diluent, 0.1-5.0 wt% of binder, and 1.0-5.0 wt% of edible essence, sweetener and/or edible pigment.
Chinese patent application CN 104367558A 1 provides an oseltamivir freeze-dried orally disintegrating tablet and a preparation method thereof, the oseltamivir freeze-dried orally disintegrating tablet is composed of oseltamivir phosphate or oseltamivir and a matrix, wherein the effective component accounts for 10-75 parts by weight of oseltamivir, the matrix contains 1-60 parts by weight of a framework support agent, 1-50 parts by weight of a binder, 0-10 parts by weight of a freeze-drying protective agent and 0-10 parts by weight of a flavoring agent, and the matrix can also contain 0-10 parts by weight of a flavoring agent and 0-69 parts by weight of an inorganic base.
However, the current oseltamivir formulations remain to be improved.
Disclosure of Invention
Summary of The Invention
The present invention is directed to solving at least one of the problems of the prior art. Therefore, the invention provides a percutaneous absorption preparation containing oseltamivir or pharmaceutically acceptable salts thereof and a preparation method thereof. The percutaneous absorption preparation can achieve the blood concentration which plays a role in prevention or treatment in a short time after administration, and release the medicine at a constant speed, thereby avoiding the peak-valley phenomenon of the oral administration of oseltamivir, maintaining the constant optimal blood concentration range, and avoiding the adverse reaction of the digestive system caused by the oral administration or the side effect caused by the sharp rise of the blood concentration; can be continuously administrated for a long time, prolong the effective action time and reduce the administration times of patients; the transdermal absorption preparation is convenient to administer, can improve the compliance of patients, can interrupt administration at any time, and improves the administration safety. In addition, the percutaneous absorption preparation can enhance the medication compliance of patients, solve the difficult problem of administration under special conditions (such as water shortage, patients with difficulty in swallowing, infants and children), avoid the bad taste caused by oral administration, and reduce the adverse reaction caused by oral administration.
Definition of terms
In the present invention, "%" means mass% unless otherwise specified.
The specific numerical values referred to in the present invention mean the numerical values. + -. 5%.
The term "optional pharmaceutically acceptable auxiliary materials" as used herein means that any pharmaceutically acceptable auxiliary materials may or may not be optionally added.
Detailed Description
It should be noted that the present invention has been completed based on the following findings of the inventors:
the existing oseltamivir preparations are basically oral preparations, and the bitter taste of oseltamivir is mostly covered by a taste-masking agent, but the bitter taste of oseltamivir cannot be completely covered by the addition of the taste-masking agent in the preparations. Meanwhile, oral administration of drugs to specific people (elderly, children and infants) or under specific conditions (water deficient conditions and dysphagia patients) is limited. However, no transdermal formulation of oseltamivir is currently on the market, and extensive studies on transdermal formulations of oseltamivir are lacking in the prior art.
In order to develop an oseltamivir transdermal drug delivery preparation for feasibility study and provide data support for the oseltamivir transdermal drug delivery, the inventor researches the skin irritation of an oseltamivir bulk drug to rabbits. The specific method comprises the following steps: the two sides of the spinal column of the back of all the experimental rabbits were depilated by electric hair clippers 24 hours before administration, with depilating areas of 3cm multiplied by 3cm at the left and right sides. The right depilating area of the back of the rabbit is set as a control area, the left side is set as a test area, a blank solvent is given to the control area, and an oseltamivir preparation is given to the test area, wherein the administration volume is 0.5 ml/time and 2 times/day, each application time is 4h, and the continuous application time is 14 days. The area of the medicine is coated by a cotton stick is 2.5cm multiplied by 2.5cm, after the medicine is coated, two layers of gauze and a layer of cellophane are used for covering, and then a non-irritant adhesive plaster and a bandage are used for fixing. Visually observing and recording whether the pasting part has erythema, edema, pigmentation, bleeding point, pachylosis and occurrence time and elimination time 1h after removing the medicine every time, before each administration and 1h, 24h, 48h and 72h after removing the medicine in the last application, and grading the erythema and the edema. Persistent lesions were present and the observation period was extended to evaluate the recovery and duration of the above changes. Results and conclusions: in the whole experiment process, no death of animals is seen, and no obvious abnormality of the body weight of the animals is seen; no toxic effects other than irritation occurred during the experiment; the integral calculation shows that the stimulation reaction integral of each animal in the administration area is 0.11 every day, and the oseltamivir API has no irritation to rabbit skin according to the stimulation intensity standard.
Further, the inventors have found through intensive studies that the drug is designed into a transdermal drug delivery preparation, and has a systemic circulation effect, the drug itself is required to have no toxic or side effect on the skin, and the drug is expected to smoothly penetrate through the stratum corneum and the active epidermis, enter the dermis and then be taken into the blood through the capillary vessels to play a role. Because of low drug loading, the drug candidates for transdermal delivery systems are generally preferred to have short half-lives, frequent administration, small daily doses (less than 20mg daily), and high efficacy.
However, since oseltamivir is administered at a high daily dose (>60mg) and is administered for a long period (at least 5 consecutive days), it is difficult to achieve a drug effective blood level after transdermal administration. The recommended dose of the oseltamivir oral preparation on the market for preventing influenza in adult and juvenile over 13 years in the influenza season is 75mg, and the dose is 1 time per day; for the treatment of influenza in adults and adolescents over 13 years of age, the recommended oral dose is 75mg each time, 2 times daily for 5 days. For children over 1 year of age, the dose is given by body weight, and at <15kg, the recommended oral dose for influenza treatment is 30mg, 2 times daily; when the dosage is more than 15-23kg, the oral administration dosage is 45mg, and the administration is carried out 2 times a day; when the dosage is more than 23-40kg, the oral administration dosage is 60mg, and the administration is carried out 2 times a day; when the dosage is more than 40kg, the oral administration dosage is 75mg, 2 times a day, and most of the oseltamivir pharmaceutically acceptable salts are compounds with good water solubility, poor fat solubility and high melting point, so that the oseltamivir compound is difficult to directly permeate the skin to enter the systemic circulation to exert the drug effect.
In view of this, the present invention provides a transdermal absorption preparation containing oseltamivir or a pharmaceutically acceptable salt thereof and a preparation method thereof. The percutaneous absorption preparation has convenient administration, can improve patient compliance, and has high drug loading (such as 7 mg/cm)2) The transdermal penetration amount of the drug is high (for example, the total release amount after 24 hours is more than 40 percent), so that the blood concentration playing a role of prevention or treatment is achieved, and the problems that the blood concentration playing a role of drug effect is difficult to achieve after the transdermal administration of the drug with high daily dose and the water-soluble drug is difficult to directly permeate the skin to enter the systemic circulation to play the role of drug effect are effectively solved. In addition, adverse reaction of digestive system during oral administration can be avoided, and a feasible administration mode is provided for treating influenza.
To this end, in one aspect of the present invention, the present invention provides a transdermal absorption preparation containing oseltamivir or a pharmaceutically acceptable salt thereof. According to an embodiment of the present invention, the transdermal absorption formulation comprises: a backing layer; a protective layer; and a pharmaceutical preparation layer located between the backing layer and the protective layer, wherein the pharmaceutical preparation layer contains oseltamivir or a pharmaceutically acceptable salt thereof. The percutaneous absorption preparation of the invention has convenient administration, can improve the compliance of patients, and has high drug loading and high percutaneous penetration of the drug, thereby achieving the blood concentration with preventive or therapeutic effect. In addition, adverse reactions of the digestive system upon oral administration can be avoided.
According to an embodiment of the present invention, the above transdermal preparation containing oseltamivir or a pharmaceutically acceptable salt thereof may further have the following additional technical features:
in some embodiments, the ratio of the weight of oseltamivir or a pharmaceutically acceptable salt thereof to the weight of the pharmaceutical formulation layer, calculated as oseltamivir free base, is: not less than 1.0%, or 10.0% -80.0%, or 30.0% -75.0%. The inventor obtains the content of the oseltamivir or the pharmaceutically acceptable salt thereof through a large number of experiments, and under the condition, the properties of the drug preparation layer can be further effectively improved, such as the solubility of the drug, the stability of the drug, the release of the drug in the patch, the transdermal permeability of the drug, the interaction between the drug preparation layer and the protective layer or the back lining layer and the cohesion of the drug preparation layer are improved.
In some embodiments, the pharmaceutical formulation layer further comprises at least one of: pressure sensitive adhesive, a framework material and a cross-linking agent. The inventor finds that the drug loading rate of the drugs in the transdermal drug delivery preparation and the release speed of the drugs in the preparation are obviously improved by adding the pressure-sensitive adhesive, the framework material and/or the cross-linking agent into the preparation, the transdermal permeation quantity of the oseltamivir is improved, so that the blood concentration with the prevention effect or the treatment effect is achieved, and the problems that the blood concentration with the drug effect difficult to achieve after transdermal drug delivery of the drugs with high daily dose and the water-soluble drugs difficult to directly permeate the skin to enter the systemic circulation to achieve the drug effect are effectively solved.
In some embodiments, the pharmaceutical formulation layer is comprised of: the oseltamivir or a pharmaceutically acceptable salt thereof; and the pressure-sensitive adhesive, wherein the weight of the pressure-sensitive adhesive accounts for the weight of the medicine preparation layer, and the weight ratio of the pressure-sensitive adhesive to the weight of the medicine preparation layer is as follows: not higher than 90.0%, or 20.0% -70.0%, or 30.0% -50.0%. The inventor obtains the components of the drug preparation layer through a large number of experiments and optimization, and under the condition, the properties of the drug preparation layer can be further effectively improved, such as the improvement of the solubility of the drug, the improvement of the stability of the drug, the promotion of the release of the drug in the patch, the enhancement of the transdermal permeability of the drug, the improvement of the interaction between the drug preparation layer and the protective layer or the back lining layer, and the improvement of the cohesive force of the drug preparation layer.
In some embodiments, the pharmaceutical formulation layer is comprised of: the oseltamivir or a pharmaceutically acceptable salt thereof; a framework material; and a cross-linking agent, wherein the weight of the framework material in the weight of the drug preparation layer is as follows: not higher than 25.0%, or 1.0% -15.0%, or 5.0% -12.0%, the weight of the cross-linking agent accounts for the weight of the drug preparation layer, and the cross-linking agent accounts for the following weight percentage: not higher than 3.0%, or 0.1% -2.5%, or 0.2% -2.0%. The inventors found that, with the above-described optimum composition of the pharmaceutical preparation layer, it is possible to further effectively improve the properties of the pharmaceutical preparation layer, such as improving the solubility of the drug, improving the stability of the drug, promoting the release of the drug in the patch, enhancing the transdermal permeability of the drug, improving the interaction between the pharmaceutical preparation layer and the protective layer or the backing layer, and improving the cohesive force of the pharmaceutical preparation layer.
In some embodiments, the pharmaceutical formulation layer is comprised of: the oseltamivir or a pharmaceutically acceptable salt thereof; a pressure sensitive adhesive; and a framework material, wherein the weight of the pressure-sensitive adhesive accounts for the weight of the pharmaceutical preparation layer in the following proportion: not higher than 90.0%, or 20.0% -70.0%, or 30.0% -50.0%, wherein the weight of the framework material accounts for the weight of the pharmaceutical preparation layer, and the weight ratio of the framework material to the pharmaceutical preparation layer is as follows: not higher than 10.0%, or 0.5% -8.0%, or 1.0% -6.0%. The inventors found that, with the above-described optimum composition of the pharmaceutical preparation layer, it is possible to further effectively improve the properties of the pharmaceutical preparation layer, such as improving the solubility of the drug, improving the stability of the drug, promoting the release of the drug in the patch, enhancing the transdermal permeability of the drug, improving the interaction between the pharmaceutical preparation layer and the protective layer or the backing layer, and improving the cohesive force of the pharmaceutical preparation layer.
In some embodiments, the pharmaceutical formulation layer further comprises a pharmaceutically acceptable excipient comprising at least one of: transdermal absorption enhancer, plasticizer, solvent, humectant, crosslinking regulator, acid, filler, antiseptic, bacteriostatic agent, antioxidant and chelating agent. The inventor finds that by adding auxiliary materials, the drug-loading rate of the drugs in the preparation and the transdermal penetration rate of the drugs are improved, so that the blood concentration with the function of prevention or treatment is achieved, and the problems that the blood concentration with the effect of the drugs with high daily dose is difficult to achieve after transdermal administration and the water-soluble drugs are difficult to directly penetrate through the skin to enter the body to circulate to exert the effect are effectively solved.
In some embodiments, the pharmaceutically acceptable salt comprises: hydrochloride, hydrobromide, sulphate, phosphate, acetate, citrate, lactate, ascorbate, maleate, tartrate, malate or succinate. The inventors found that, under such conditions, the properties of the drug formulation layer can be further effectively improved, for example, the solubility of the drug can be improved, the stability of the drug can be improved, the release of the drug in the patch can be promoted, the transdermal permeability of the drug can be enhanced, the interaction between the drug formulation layer and the protective layer or the backing layer can be improved, and the cohesion of the drug formulation layer can be improved.
In some embodiments, the pressure sensitive adhesive includes, but is not limited to, acrylic polymers (e.g., DURO-TAK 87-2194, DURO-TAK 387 2287, DURO-TAK 87-2852), methacrylic polymers, polyisobutylene polymers, rubbers (e.g., natural rubber, synthetic rubber-SIS), and silicones (e.g., Dow)
BIO-PSAQ7-2920, BIO-PSAQ7-2675, BIO-PSA4301, BIO-PSA4302, BIO-PSA4201, BIO-PSA4202, BIO-PSA4101, BIO-PSA4102, BIO-PSA4601, BIO-PSA4602, BIO-PSA4501, BIO-PSA4502, BIO-PSA4401, BIO-PSA4402), or mixtures thereof. Therefore, the properties of the drug preparation layer can be further effectively improved, such as the improvement of the solubility of the drug, the improvement of the stability of the drug, the promotion of the release of the drug in the patch, the enhancement of the transdermal permeability of the drug, the improvement of the interaction between the drug preparation layer and the protective layer or the back lining layer, and the improvement of the cohesion of the drug preparation layer.
In some embodiments, the matrix material (including, but not limited to, polyvinyl alcohol, polyacrylic acid, sodium polyacrylate, partially neutralized sodium polyacrylate (e.g., NP-600/700/800), acrylic acid copolymers, methacrylic acid copolymers, acrylic acid and methacrylic acid copolymers, acrylates, phthalates, gelatin, tragacanth, agar, carbomer, hydroxypropyl methylcellulose, povidone (XL, K90), sodium carboxymethylcellulose, polyethylene glycol, or mixtures thereof) is crosslinked with a crosslinking agent (including, but not limited to, aluminum glycollate, aluminum hydroxide gel hydroxide, magnesium aluminum silicate, calcium hydroxide, magnesium aluminate, aluminum chloride, aluminum potassium sulfate, aluminum nitrate, calcium chloride, calcium nitrate, aluminum glycinate, magnesium aluminum silicate, magnesium aluminum carbonate, or mixtures thereof) to form a matrix. Therefore, the properties of the drug preparation layer can be further effectively improved, such as the improvement of the solubility of the drug, the improvement of the stability of the drug, the promotion of the release of the drug in the patch, the enhancement of the transdermal permeability of the drug, the improvement of the interaction between the drug preparation layer and the protective layer or the back lining layer, and the improvement of the cohesion of the drug preparation layer.
In some embodiments, the transdermal absorption enhancers include, but are not limited to, pyrrolidones (e.g., 2-pyrrolidone, N-methylpyrrolidone), Azone and analogs thereof (e.g., Azone, HPE-101), fatty acids and esters thereof (e.g., esters of oleic acid, lauric acid, oleic acid, or lauric acid, isopropyl myristate, propylene glycol fatty acid esters, glycerin fatty acid esters, sorbitan fatty acid esters, polyethylene glycol glycerides oleate, polyglycerol-3 diisostearate, polyglycerol oleate, polyethylene glycol glycerides caprylate caprite, sodium lauryl sulfate), ethers (e.g., poloxamer, polyoxypropylene stearyl ether), alcohols (e.g., ethanol, isopropanol), polyols (e.g., propylene glycol, glycerin, 1, 3-butylene glycol), terpenes (e.g., menthol, eucalyptus oil), amines (e.g., urea, dodecyl-N, N-dimethylaminoethyl ester), amides (e.g., dimethylformamide, dimethylacetamide), phospholipids (e.g., lecithin, phosphatidylglycerol), or mixtures thereof. According to a specific embodiment of the present invention, the transdermal absorption enhancer accounts for 0.5% to 15%, or 1.0% to 10.0%, or 2.0% to 8.0% of the weight of the drug preparation layer. Therefore, the properties of the drug preparation layer can be further effectively improved, such as the improvement of the solubility of the drug, the improvement of the stability of the drug, the promotion of the release of the drug in the patch, the enhancement of the transdermal permeability of the drug, the improvement of the interaction between the drug preparation layer and the protective layer or the back lining layer, and the improvement of the cohesion of the drug preparation layer.
In some embodiments, the plasticizer includes, but is not limited to, petroleum-based oils, squalane, squalene, vegetable-based oils, silicone oils, dibasic esters, liquid rubbers, liquid fatty acid esters, diethylene glycol, polyethylene glycol, propylene glycol, glycerin, or mixtures thereof. Therefore, the properties of the drug preparation layer can be further effectively improved, such as the improvement of the solubility of the drug, the improvement of the stability of the drug, the promotion of the release of the drug in the patch, the enhancement of the transdermal permeability of the drug, the improvement of the interaction between the drug preparation layer and the protective layer or the back lining layer, and the improvement of the cohesion of the drug preparation layer.
In some embodiments, the solvent includes, but is not limited to, water, ethanol, propylene glycol, heptane, acetone, methanol, ethyl acetate, or mixtures thereof. Therefore, the solubility of oseltamivir can be improved, the coating performance of a medicine preparation layer is improved, the transdermal permeability of medicines is enhanced, the interaction between the medicine preparation layer and a protective layer or a back lining layer is improved, and the cohesive force of the medicine preparation layer is improved.
In some embodiments, the filler includes, but is not limited to, kaolin, zinc oxide, aerosil, calcium carbonate, kaolin, bentonite, titanium dioxide, or mixtures thereof. Thereby, the properties of the drug formulation layer can be further effectively improved, for example, the stability of the drug is improved, the interaction between the drug formulation layer and the protective layer or the backing layer is improved, and the cohesive force of the drug formulation layer is improved.
In some embodiments, the humectant includes, but is not limited to, glycerin, propylene glycol, polyethylene glycol, hyaluronic acid, or mixtures thereof. Therefore, the properties of the drug preparation layer can be further effectively improved, such as the improvement of the solubility of the drug, the improvement of the stability of the drug, the promotion of the release of the drug in the patch, the enhancement of the transdermal permeability of the drug, the improvement of the interaction between the drug preparation layer and the protective layer or the back lining layer, and the improvement of the cohesion of the drug preparation layer.
In some embodiments, the acid includes, but is not limited to, tartaric acid, lactic acid, oleic acid, succinic acid, acetic acid, malic acid, citric acid, hydrochloric acid, phosphoric acid, ascorbic acid, maleic acid, or mixtures thereof. Therefore, the properties of the drug preparation layer can be further effectively improved, such as the improvement of the solubility of the drug, the improvement of the stability of the drug, the promotion of the release of the drug in the patch, the enhancement of the transdermal permeability of the drug, the improvement of the interaction between the drug preparation layer and the protective layer or the back lining layer, and the improvement of the cohesion of the drug preparation layer.
In some embodiments, the preservative or bacteriostatic agent includes, but is not limited to, methylparaben, propylparaben, butylparaben, sorbic acid, benzoic acid, benzyl alcohol, imidurea, benzyl alcohol, or mixtures thereof. Thereby, the properties of the drug formulation layer can be further effectively improved, for example, the stability of the drug can be improved.
In some embodiments, the antioxidants include, but are not limited to, propyl gallate, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), citric acid, EDTA and salts thereof, tocopherols, or mixtures thereof. Thereby, the properties of the drug formulation layer can be further effectively improved, for example, the stability of the drug can be improved. In addition, EDTA and its salts can also function as chelating agents.
The thickness of the drug preparation layer is not strictly limited, and can be appropriately determined by those skilled in the art based on factors such as the amount of the drug. According to a specific embodiment of the present invention, the thickness of the pharmaceutical preparation layer is 10 to 4000 μm, or 20 to 3000 μm. Thereby, the properties of the drug preparation layer can be further effectively improved, for example, the release of the drug in the patch is promoted, and the transdermal permeability of the drug is enhanced.
The protective layer of the present invention is an anti-adhesive material for protecting the drug-containing layer of the formulation, and in practical applications, those skilled in the art can select the protective layer of the best material according to the properties of the specific drug formulation layer or the backing layer. Specifically, the material should have good compatibility with the drug preparation layer or the backing layer, and should be an inert, opaque or light-shielding metal-plated polyester film, and the material may be one or more of polyethylene terephthalate, aluminum foil, polyethylene-aluminum composite film, and polyethylene-glassine-polyethylene composite film. The surface of the protective layer that is in contact with the pharmaceutical preparation layer may be coated with a polymer such as silicone, fluorosilicone, or perfluorocarbon polymer that prevents sticking of the pressure-sensitive adhesive. The protective layer adheres firmly to the surface of the drug formulation layer or the backing layer prior to use and is easily peeled from the drug formulation layer or the backing layer during use. The thickness of the protective layer may be appropriately determined by those skilled in the art.
The backing layer in the present invention is a film supporting the drug preparation layer, and the backing layer may be, but not limited to, an organic polymer film, a metal foil or an organic polymer film, a laminated film of a metal foil, a nonwoven fabric, or the like. Wherein the organic polymer film may be a film made of, but not limited to, cellulose acetate, ethyl cellulose, polyester, nylon, polyvinyl chloride, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene-propylene copolymer, vinyl acetate-vinyl chloride copolymer, polyethylene terephthalate, polytetrafluoroethylene, or ionomer resin. The ideal backing material requirements are: has good compatibility with medicines and auxiliary materials; a thickness of about 75 μm; low moisture transmission rate: (<20g/m224 h); the oxygen transmission rate is high, the skin hydration effect is improved, and the normal breathing of the skin can be ensured; no toxicity; a color acceptable to the patient or transparent or translucent; low halo brightness<10 percent; the feeling of being stuck on the skin is good; the texture is firm and smooth, and the feeling of dryness is felt by touch; good tear strength and heat sealability. In practical applications, the backing layer of the optimal material needs to be selected according to the nature of the drug preparation layer or the protective layer and the adhesion time, and the thickness can be determined by those skilled in the art. In particular, the backing layer may be 3M CoTranTM9700、3M CoTranTM9701、3M CoTranTM9718、3M CoTranTM9719、3M CoTranTM9720、3M CoTranTM9722、3M CoTranTM9726。
The transdermal preparation may be a patch or a patch, but is not limited to these two transdermal preparations.
In some embodiments, the transdermal formulations of the present invention comprise: a backing layer; a protective layer; and a pharmaceutical formulation layer comprising:
the weight of the oseltamivir or the pharmaceutically acceptable salt thereof accounts for 10.0 to 78.0 percent of the weight of the medicinal preparation layer, calculated as oseltamivir free alkali;
the weight of the pressure sensitive adhesive accounts for 22.0-90.0% of the weight of the medicinal preparation layer.
The percutaneous absorption preparation of the invention has convenient administration, can improve the compliance of patients, and has high drug loading and high percutaneous penetration of the drug, thereby achieving the blood concentration with preventive or therapeutic effect. In addition, adverse reactions of the digestive system upon oral administration can be avoided.
In some embodiments, the transdermal formulations of the present invention comprise: a backing layer; a protective layer; and a drug formulation layer, wherein:
the weight of the oseltamivir or the pharmaceutically acceptable salt thereof accounts for 48.6 percent of the weight of the medicinal preparation layer calculated according to the oseltamivir free alkali;
the weight of the pressure sensitive adhesive accounts for 46.60% of the weight of the pharmaceutical preparation layer;
the weight ratio of the transdermal absorption enhancer to the weight of the drug preparation layer is 4.8%.
The percutaneous absorption preparation of the invention has convenient administration, can improve the compliance of patients, and has high drug loading and high percutaneous penetration of the drug, thereby achieving the blood concentration with preventive or therapeutic effect. In addition, adverse reactions of the digestive system upon oral administration can be avoided.
In some embodiments, the transdermal formulations of the present invention comprise: a backing layer; a protective layer; and a drug formulation layer, wherein:
the weight of the oseltamivir or the pharmaceutically acceptable salt thereof accounts for 53.89 to 59.3 percent of the weight of the medicinal preparation layer calculated by the oseltamivir free alkali;
the weight of the pressure-sensitive adhesive accounts for 36.2 to 41.6 percent of the weight of the medicinal preparation layer;
the transdermal absorption enhancer accounts for 4.5% of the weight of the drug preparation layer.
The percutaneous absorption preparation of the invention has convenient administration, can improve the compliance of patients, and has high drug loading and high percutaneous penetration of the drug, thereby achieving the blood concentration with preventive or therapeutic effect. In addition, adverse reactions of the digestive system upon oral administration can be avoided.
In some embodiments, the transdermal formulations of the present invention comprise: a backing layer; a protective layer; and a drug formulation layer, wherein:
the weight of the oseltamivir or the pharmaceutically acceptable salt thereof accounts for 10.0 to 50.2 percent of the weight of the medicinal preparation layer, calculated as oseltamivir free alkali;
the weight of the pressure sensitive adhesive accounts for 49.8-90.0% of the weight of the medicinal preparation layer.
The percutaneous absorption preparation of the invention has convenient administration, can improve the compliance of patients, and has high drug loading and high percutaneous penetration of the drug, thereby achieving the blood concentration with preventive or therapeutic effect. In addition, adverse reactions of the digestive system upon oral administration can be avoided.
In some embodiments, the transdermal formulations of the present invention comprise: a backing layer; a protective layer; and a drug formulation layer, wherein:
the weight of the oseltamivir or the pharmaceutically acceptable salt thereof accounts for 7.76 to 25.20 percent of the weight of the medicinal preparation layer, calculated as oseltamivir free alkali;
the weight of the pressure-sensitive adhesive accounts for 48.3 to 69.4 percent of the weight of the medicinal preparation layer;
the weight of the plasticizer accounts for 9.3 to 10.2 percent of the weight of the medicinal preparation layer;
the weight of the solvent accounts for 9.3 to 10.2 percent of the weight of the medicinal preparation layer.
The percutaneous absorption preparation of the invention has convenient administration, can improve the compliance of patients, and has high drug loading and high percutaneous penetration of the drug, thereby achieving the blood concentration with preventive or therapeutic effect. In addition, adverse reactions of the digestive system upon oral administration can be avoided.
In some embodiments, the transdermal formulations of the present invention comprise: a backing layer; a protective layer; and a drug formulation layer, wherein:
the weight of the oseltamivir or the pharmaceutically acceptable salt thereof accounts for 1.52 to 3.81 percent of the weight of the medicinal preparation layer, calculated as the oseltamivir free alkali;
the weight of the humectant accounts for 30.0 percent of the weight of the medicinal preparation layer;
the weight of the framework material accounts for 6.2 to 10.0 percent of the weight of the medicinal preparation layer;
the weight of the cross-linking agent accounts for 0.15 to 0.2 percent of the weight of the medicinal preparation layer;
the weight of the solvent accounts for 55.39-61.2% of the weight of the medicinal preparation layer;
the weight of the acid accounts for 0.18 to 0.2 percent of the weight of the medicinal preparation layer;
the chelating agent accounts for 0.18 to 0.2 percent of the weight of the medicinal preparation layer.
The percutaneous absorption preparation of the invention has convenient administration, can improve the compliance of patients, and has high drug loading and high percutaneous penetration of the drug, thereby achieving the blood concentration with preventive or therapeutic effect. In addition, adverse reactions of the digestive system upon oral administration can be avoided.
In another aspect of the present invention, the present invention provides a method for preparing the above-described transdermal absorption preparation containing oseltamivir or a pharmaceutically acceptable salt thereof. According to an embodiment of the invention, the method comprises: (1) providing a backing layer and a protective layer; (2) coating the medicinal preparation solution containing oseltamivir or the acceptable salt thereof on the back lining layer or the protective layer, and standing or drying; and (3) laminating the backing layer and the protective layer to obtain the percutaneous absorption preparation, wherein the pharmaceutical preparation solution containing oseltamivir or a pharmaceutically acceptable salt thereof is obtained by mixing: oseltamivir or a pharmaceutically acceptable salt thereof; at least one of a pressure sensitive adhesive, a backbone material, and a crosslinking agent; and optionally pharmaceutically acceptable excipients. Therefore, the method provided by the embodiment of the invention is simple and convenient to operate and is suitable for industrial production. The obtained percutaneous absorption preparation is convenient to administer, can improve the compliance of patients, and has high drug loading and high percutaneous penetration, thereby achieving the blood concentration with prevention or treatment effect. In addition, adverse reactions of the digestive system upon oral administration can be avoided.
It should be noted that, those skilled in the art can select the mixing mode according to the actual needs, and can mix all the pharmaceutical preparations simultaneously, or can mix all the pharmaceutical preparations according to the physicochemical properties of the components.
It will be appreciated by those skilled in the art that the features and advantages described above for a transdermal formulation comprising oseltamivir or a pharmaceutically acceptable salt thereof are equally applicable to the method for preparing a transdermal formulation comprising oseltamivir or a pharmaceutically acceptable salt thereof and will not be described in detail herein.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
FIG. 1 shows Franz diffusion cells used during transdermal experimental investigations according to embodiments of the present invention;
FIG. 2 is a graph showing the cumulative skin permeation amount per unit area of oseltamivir in transdermal preparations of different formulations obtained by examination according to an embodiment of the present invention as a function of time; and
fig. 3 is a graph showing the cumulative skin permeation amount per unit area of oseltamivir in the transdermal absorption preparations containing different kinds of transdermal absorption enhancers examined according to the examples of the present invention as a function of time.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
Example 1
Layer prescription of pharmaceutical preparation:
the preparation method comprises the following steps:
mixing oseltamivir and ethyl acetate, sequentially adding acrylate pressure-sensitive adhesive (LOCTITE DURO-TAK2852), stirring, and coating on 3M CoTranTM9748 on a release film (protective layer), drying (ethyl acetate is evaporated and removed, not included in the prescription), and mixing with 3M ScotchpakTM9735 the back lining layers are laminated to obtain the percutaneous absorption preparation with prescription 1-8.
Example 2
Layer prescription of pharmaceutical preparation:
the preparation method comprises the following steps:
mixing oseltamivir and ethyl acetate, adding pressure sensitive adhesive (LOCTITE DURO-TAK2852), stirring, adding N-methylpyrrolidone/diethylene glycol monoethyl ether/PEG 4000/citric acid/PVP K90/oleic acid, stirring, and coating on 3M CoTranTM9748 on a release film (protective layer), drying (ethyl acetate is evaporated and removed, not included in the prescription), and mixing with 3M ScotchpakTM9735 backingLaminating the layers to obtain the percutaneous absorption preparation with the formula of 9-14.
Example 3
Layer prescription of pharmaceutical preparation:
the preparation method comprises the following steps:
mixing oseltamivir and ethyl acetate, adding pressure sensitive adhesive (LOCTITE DURO-TAK2852), stirring, adding oleic acid, stirring, and coating on 3M CoTranTM9748 on a release film (protective layer), drying (ethyl acetate is evaporated and removed, not included in the prescription), and mixing with 3M ScotchpakTM9735 backing layers are laminated to obtain transdermal preparations of formulas 15 and 16.
Example 4
Layer prescription of pharmaceutical preparation:
the preparation method comprises the following steps:
mixing oseltamivir and ethyl acetate uniformly, adding pressure-sensitive adhesive, stirring uniformly, and coating on 3M CoTranTM9748 on a release film (protective layer), drying (ethyl acetate is evaporated and removed, not included in the prescription), and mixing with 3M ScotchpakTM9735 the back lining layers are laminated to obtain the percutaneous absorption preparation with formula 17-21.
Example 5
Layer prescription of pharmaceutical preparation:
the preparation method comprises the following steps:
mixing oseltamivir phosphate and purified water, sequentially adding glycerol and silicone pressure sensitive adhesive (BIO-PSA4301), stirring, and coating on 3M ScotchpakTM1022 release typeOn film, dried, and reacted with 3M CoTranTM9726 the back layers are laminated to obtain percutaneous absorption preparations of formulas 22 and 23.
Example 6
Layer prescription of pharmaceutical preparation:
the preparation method comprises the following steps:
1) adding carbomer 980 into water, and swelling to obtain phase one;
2) mixing aluminum glycerolate and EDTA-Na2Dispersing in glycerol, and adding NP-700 to disperse uniformly to obtain phase two;
3) dissolving polyvidone K90 and D-tartaric acid in appropriate amount of water, swelling, adding oseltamivir phosphate, stirring, and dissolving to obtain phase III;
4) adding the first phase into the second phase in batches, stirring uniformly to obtain a mixture, adding the third phase into the mixture, stirring uniformly, coating on a spunlace non-woven fabric, and covering with a 3M ScotchpakTM1022 release film to obtain percutaneous absorption preparations of formulas 24 and 25.
Example 7
Skin irritation test in rabbits
The osletamivir transdermal patch obtained according to the formulas 1, 4, 7, and 8 was examined for skin irritation after a single administration.
Experimental animals: a healthy rabbit.
Purpose of the experiment: the effect of high, medium and low drug loading patches and drug-free patches (vehicle group) on rabbit skin irritation was examined.
The experimental method comprises the following steps:
the test preparations were applied to healthy and injured skin on the back of rabbits for 24 hours, and skin symptoms after peeling for 1 hour, 24 hours, and 48 hours were visually judged according to the scoring criteria in table 1, and the irritation index of each test preparation was calculated. The skin irritation intensity was determined according to table 2.
The stimulation index calculation method comprises the following steps: skin irritation index ═ total irritation value/number of observations;
1. the values observed after 1h, 24h, 48h after patch removal were added for each rabbit to determine the combined irritation value for the erythema or eschar formation fraction.
2. For each rabbit, the values observed after 1h, 24h, 48h after patch removal were added to determine the combined irritation values of the edema-forming moieties.
3. For each rabbit, the combined irritation value of the erythema-or eschar-forming fraction was added to the combined irritation value of the edema-forming fraction, and the total irritation value for each rabbit was calculated.
TABLE 1 skin irritation response Scoring criteria
TABLE 2 evaluation criteria for skin irritation intensity
| Score value | Evaluation of |
| 0～0.49 | Has no irritation |
| 0.5～2.99 | Mild irritation |
| 3.0～5.99 | Moderate irritation |
| 6.0～8.0 | Strong irritation |
The experimental results are as follows:
| | Prescription | 1 | |
Prescription 7 | Prescription 8 (excipient group) |
| Stimulation index | 0.48 | 0.42 | 0.33 | 0.21 |
From the above results, it was confirmed that the preparations of the present invention having high, medium and low drug-loading amounts and the excipient group preparations were not irritating to rabbit skin, indicating that both pressure-sensitive adhesive and drug-containing pressure-sensitive adhesive having different drug-loading amounts had good safety.
Example 8
In vitro percutaneous permeation behavior investigation
The oseltamivir transdermal patch obtained according to prescription 4, prescription 9, prescription 10, prescription 14, prescription 15 and prescription 16 is inspected, and punched out into a suitable size (e.g., 1.4 × 1.4 cm)2) Adhering to in vitro skin, and examining different prescription ratiosThe effect of the example oseltamivir and different kinds of transdermal absorption enhancers on the transdermal penetration of the patch in vitro.
Experimental animals: bama miniature pig flank skin
Experimental apparatus and conditions:
as shown in FIG. 1, the Franz diffusion cell has a supply chamber 100, a drug delivery system 200, a thermostatic waterbath 300, skin 400, a sampling port 500, a receiving chamber 600, a star stirrer 700, a receiving chamber volume of 7ml, and a waterbath temperature of 37 + -0.5 ℃. Fixing skin between the supply chamber and the receiving chamber, with stratum corneum facing upwards, the receiving solution is phosphate buffer solution with pH7.4, peeling off the protective layer of the oseltamivir transdermal absorption patch, adhering and fixing on the skin in the supply chamber, starting magnetic stirring at 200rpm, taking 2.0ml of the receiving solution at 30min, 1h, 2h, 4h, 6h, 8h, 12h and 24h respectively, simultaneously supplementing equal amount of phosphate buffer solution with pH7.4, and analyzing the sample by HPLC.
The HPLC chromatographic conditions were as follows:
the instrument comprises the following steps: agilent 1260 HPLC-DAD;
a chromatographic column: agilent ZORBAX Eclipse XDB-C18, 4.6 x 150mm, 5 μm;
mobile phase: methanol-acetonitrile-potassium dihydrogen phosphate buffer (pH 6.0) 245:135: 620;
diluent agent: phosphate buffer (0.05M potassium dihydrogen phosphate solution + NaOH) at pH 7.4;
flow rate: 1.2 ml/min;
column temperature: 50 ℃;
sample introduction amount: 15 μ l
Detection wavelength: 207 nm;
temperature of the sample pan: 4 ℃;
operating time: 12 min;
and (3) an elution mode: isocratic elution.
The experimental results are as follows:
FIG. 2 is a graph showing the cumulative skin permeation amount per unit area versus time for oseltamivir patches (oseltamivir in different prescription ratios) prepared according to prescription 14, prescription 15 and prescription 16 in examples of the present invention; wherein the content of oseltamivir in the patch obtained by the prescription 16 is the highest, and the content of oseltamivir in the patch obtained by the prescription 14 is the lowest. As shown in fig. 2, the patch obtained by the formula 16 has the highest skin permeation amount per unit area within 24h, and the patch obtained by the formula 14 has the lowest skin permeation amount per unit area, which indicates that the drug content in the patch is increased, and the skin permeation amount per unit area of oseltamivir can be obviously increased.
Fig. 3 shows a graph of cumulative skin permeation per unit area versus time for oseltamivir patches prepared according to formulation 4, formulation 9, formulation 10 and formulation 14 in the examples of the present invention, and the influence of different kinds of transdermal absorption enhancers on the skin permeation performance of oseltamivir patches was examined. Prescription 9 contains transdermal absorption enhancer N-methyl pyrrolidone; the prescription 10 contains a transdermal absorption enhancer of diethylene glycol monoethyl ether; formula 14 contains oleic acid, a transdermal absorption enhancer; prescription 4 contains no percutaneous absorption enhancer, and is used as control group. The results show that the patch prepared by the prescription 14 (containing oleic acid) has the highest skin cumulative permeation amount per unit area, and compared with the prescription 4, the skin cumulative permeation amount per unit area of oseltamivir in the patch can be obviously improved; the patch obtained by the prescription 9 (containing N-methyl pyrrolidone) can improve the accumulated skin permeation amount per unit area of oseltamivir in the patch compared with the patch obtained by the prescription 4; in contrast, in the patch of formula 10 (containing diethylene glycol monoethyl ether), the amount of accumulated skin permeation per unit area of oseltamivir in the patch was decreased as compared with that of formula 4. The experimental results show that the skin permeation amount of the medicine in the patch can be obviously improved by selecting the proper transdermal absorption enhancer, but the skin permeation amount of the medicine in the patch can not be improved by selecting the improper transdermal absorption enhancer, and even the skin permeation amount of the medicine in the patch can be reduced.
As described in the foregoing examples, according to the transdermal preparation provided by the present invention, oseltamivir, which is an active ingredient, can be efficiently absorbed through the skin in the circulating blood. In addition, adverse reaction of digestive system during oral administration can be avoided, side effect caused by rapid rise of blood concentration can be avoided, and a feasible administration mode is provided for treating influenza.
In the description herein, references to the description of "one embodiment," "some embodiments," or "a specific embodiment," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (8)
1. A percutaneous absorption preparation containing oseltamivir or a pharmaceutically acceptable salt thereof, comprising:
a backing layer;
a protective layer; and
a drug preparation layer which is positioned between the back lining layer and the protective layer, wherein the drug preparation layer consists of oseltamivir or pharmaceutically acceptable salt thereof, pressure-sensitive adhesive and transdermal absorption enhancer,
wherein, the weight of the oseltamivir or the pharmaceutically acceptable salt thereof accounts for 30.0 to 75.0 percent of the weight of the medicinal preparation layer calculated by the oseltamivir free alkali;
the pressure-sensitive adhesive is an acrylic polymer, and the weight of the pressure-sensitive adhesive accounts for 20.0-70.0% of the weight of the pharmaceutical preparation layer;
the transdermal absorption enhancer is selected from pyrrolidone or fatty acid, and the weight of the transdermal absorption enhancer accounts for 0.5-15% of the weight of the medicinal preparation layer.
2. The percutaneous absorption preparation according to claim 1, wherein the proportion of the weight of the pressure-sensitive adhesive to the weight of the drug preparation layer is 30.0% to 50.0%, and/or the proportion of the weight of the percutaneous absorption enhancer to the weight of the drug preparation layer is 1.0% to 10.0%.
3. The percutaneous absorption preparation according to claim 1, wherein the acrylic polymer is selected from the group consisting of LOCTITE DURO-TAK 2194, LOCTITE DURO-TAK2852, and LOCTITE DURO-TAK 2287.
4. The percutaneous absorption preparation according to claim 1, wherein the pyrrolidone is selected from the group consisting of 2-pyrrolidone and N-methylpyrrolidone.
5. The percutaneous absorption preparation according to claim 1, wherein the fatty acid is selected from oleic acid and lauric acid.
6. The percutaneous absorption preparation according to claim 1, wherein the pharmaceutically acceptable salt comprises:
hydrochloride, hydrobromide, sulphate, phosphate, acetate, citrate, lactate, ascorbate, maleate, tartrate, malate or succinate.
7. The percutaneous absorption preparation according to claim 1, wherein the thickness of the drug preparation layer is 10 to 4000 μm.
8. A process for preparing the transdermal preparation comprising oseltamivir or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, which comprises:
(1) providing a backing layer and a protective layer;
(2) coating a medicinal preparation solution containing oseltamivir or pharmaceutically acceptable salts thereof on the back lining layer or the protective layer, and standing or drying; and
(3) laminating the backing layer with the protective layer to obtain the percutaneous absorption preparation,
wherein the pharmaceutical preparation solution containing oseltamivir or a pharmaceutically acceptable salt thereof is obtained by mixing:
oseltamivir or a pharmaceutically acceptable salt thereof;
a pressure sensitive adhesive; and a transdermal absorption enhancer.
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| CN1633994A (en) * | 2004-11-04 | 2005-07-06 | 中国人民解放军总医院 | Compound control-released percutaneous medicine plaster for treating high blood pressure and its preparation method |
| CN102225058A (en) * | 2011-06-22 | 2011-10-26 | 中国药科大学 | Oseltamivir phosphate dry powder inhalations and preparation method thereof |
| KR20120056322A (en) * | 2010-11-25 | 2012-06-04 | 대화제약 주식회사 | Transdermal system of zanamivir as active ingredient |
| CN102497852A (en) * | 2009-02-10 | 2012-06-13 | Lts勒曼治疗系统股份公司 | N-hydroxylated amidine-, guanidine- and/or aminohydrazone-type prodrugs for application on the skin |
| CN104387288A (en) * | 2014-11-25 | 2015-03-04 | 广东东阳光药业有限公司 | Compound as neuraminidase inhibitor and application of compound in medicine |
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| US20070190124A1 (en) * | 2004-06-07 | 2007-08-16 | Jie Zhang | Two or more solidifying agent-containing compositions and methods for dermal delivery of drugs |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1633994A (en) * | 2004-11-04 | 2005-07-06 | 中国人民解放军总医院 | Compound control-released percutaneous medicine plaster for treating high blood pressure and its preparation method |
| CN102497852A (en) * | 2009-02-10 | 2012-06-13 | Lts勒曼治疗系统股份公司 | N-hydroxylated amidine-, guanidine- and/or aminohydrazone-type prodrugs for application on the skin |
| KR20120056322A (en) * | 2010-11-25 | 2012-06-04 | 대화제약 주식회사 | Transdermal system of zanamivir as active ingredient |
| CN102225058A (en) * | 2011-06-22 | 2011-10-26 | 中国药科大学 | Oseltamivir phosphate dry powder inhalations and preparation method thereof |
| CN104387288A (en) * | 2014-11-25 | 2015-03-04 | 广东东阳光药业有限公司 | Compound as neuraminidase inhibitor and application of compound in medicine |
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