TWI776093B - Use of ginkgo extracts for preparing a pharmaceutical composition for treating ischemia - Google Patents

Abstract

The disclosure provides a pharmaceutical composition for ischemia treatment of a patient. The pharmaceutical composition includes ginkgo extraction and a pharmaceutically acceptable carrier. Wherein the dosage form of the pharmaceutical composition is gel, transdermal patch, cream or paste. The patient is a neonate, an infant, or an early child. The disclosure further provides a use of the ginkgo extraction for manufacturing the pharmaceutical composition for ischemia treatment of a patient. The application of the pharmaceutical composition and the use of the present invention are advantageous for treating ischemia.

Description

Use of Ginkgo biloba extract for preparing medicinal composition for treating ischemia

The present invention relates to a medicinal composition for treating ischemia and the use of preparing the medicinal composition.

Ischemia refers to a decrease in blood volume in an organ or tissue, which can be a local manifestation of generalized anemia or the result of a local disturbance of blood circulation. Depending on where the ischemia occurs, it can be divided into limb ischemia or organ ischemia, such as cerebral ischemia (ischemic stroke), cardiac ischemia (ischemic heart disease), and the like. In recent years, the incidence of peripheral arterial occlusive disease has increased due to population aging, smoking, changes in dietary habits, and the increase in the proportion of the diabetic population, which in turn leads to an increase in the incidence of limb ischemia, which may even be as high as 11 %. In addition to peripheral arterial occlusive disease, Raynaud's phenomenon, Berger's disease, vasospasm, and compression may also lead to limb ischemia.

Limb ischemia may also occur in neonates, especially preterm infants. The cause is different from that of adults, which may be caused by vascular hypoplasia, hypoxia, anemia, etc. However, whether it is an adult or a newborn, limb ischemia may cause numbness, pain or coldness in the limbs. With the increase of ischemia time, it is more likely to cause the limbs to become purple, black, and even tissue ulceration and necrosis.

Traditionally, ischemia is primarily treated with oral drugs, however, orally administered drugs act not only at the site of ischemia, but throughout the body. Therefore, systemic or systemic side effects may occur, and the speed and efficacy of the drug may be affected by the organs that metabolize the drug (eg, liver, kidney, etc.).

Therefore, there is still an urgent need for a pharmaceutical composition for the treatment of ischemia and its preparation application, which can directly act on the ischemic tissue to promote its blood circulation, so as to avoid local tissue Ischemia causes numbness, pain, and even purple, black, ulceration or necrosis, thereby achieving the effect of treating local ischemia, and at the same time avoiding side effects caused by drugs acting on other tissues.

In view of the above-mentioned problems, the purpose of the present invention is to provide a pharmaceutical composition for treating ischemia and its preparation application. The pharmaceutical composition can directly act on ischemic tissue to promote its blood circulation, so as to avoid localized ischemia. The tissue is numb, painful, cold, even purple, black, ulcerated, and necrotic due to ischemia, so as to achieve the effect of treating local ischemia, and at the same time, it can avoid the side effects caused by the drug acting on other tissues.

In order to achieve the above object, the present invention provides a pharmaceutical composition for treating ischemia, which is used for a patient suffering from ischemia. The pharmaceutical composition comprises a ginkgo biloba extract and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is The dosage form of the drug is gel, transdermal patch, cream or ointment. The patient is a newborn, infant or toddler.

In order to achieve the above purpose, the present invention further provides the use of a ginkgo extract for preparing a medicinal composition for treating ischemia, the medicinal composition is used for a patient suffering from ischemia, and the medicinal composition comprises a ginkgo extract and A pharmaceutically acceptable carrier, wherein the dosage form of the pharmaceutical composition is gel, transdermal patch, cream or ointment. The patient is a newborn, infant or toddler.

In one embodiment, the Ginkgo biloba extract is extracted from Ginkgo biloba leaves, and includes more than 20% flavonoid glycosides and more than 5% ginkgolides.

In one embodiment, the dosage of Ginkgo biloba extract is between 0.01 mg/ml and 5 mg/ml.

In one embodiment, the dosage of Ginkgo biloba extract is between 0.01 mg/cm 2 and 5 mg/cm 2 .

In one embodiment, the pharmaceutically acceptable carrier is mineral oil, propylene glycol, polyoxypropylene, emulsifying wax, glycerin, polyethylene glycol, fatty alcohol, fatty ether, fatty acid ester, vegetable oil, silicone oil, petrolatum , lanolin, beeswax, hyaluronic acid, polyacrylic acid, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl methylcellulose or carboxypropyl methyl base cellulose.

Continuing from the above, the effect of the present invention is: by providing a pharmaceutical composition for treating ischemia and its preparation application, it can directly act on the ischemic tissue to promote the blood circulation of the local tissue, so as to avoid local ischemia. The tissue is numb, painful, or even purple, black, ulcerated or necrotic due to ischemia, thereby achieving the effect of treating local ischemia, and at the same time avoiding side effects caused by drugs acting on other tissues.

The preferred embodiments and experimental examples of the pharmaceutical composition for treating ischemia and its preparation and use according to the present invention will be described below with reference to the relevant tables, wherein the same elements will be described with the same reference symbols.

The pharmaceutical composition of the present invention and its preparation application can directly act on the ischemic tissue to promote the blood circulation of the local tissue, so as to avoid numbness, pain, or even purple, black, ulceration or necrosis, thereby achieving the effect of treating ischemia, and at the same time avoiding side effects caused by drugs acting on other tissues.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the testing experiments of the present invention, the preferred materials and methods are described herein. In describing and claiming the present invention, the following terminology will be used. It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and not for the purpose of limiting the invention.

The term "ischemia" refers to a decrease in blood volume in an organ or tissue, which can be a local manifestation of generalized anemia, or the result of a local disturbance of blood circulation. Depending on where the ischemia occurs, it can be divided into limb ischemia or organ ischemia, such as cerebral ischemia (ischemic stroke), cardiac ischemia (ischemic heart disease), and the like. Limb ischemia may be caused by peripheral arterial occlusive disease, Raynaud's phenomenon, Berger's disease, vasospasm, compression, vascular hypoplasia, hypoxia, anemia, etc. Limb ischemia may cause numbness, pain or coldness at the end of the limb, and with the increase of ischemia time, it is more likely to cause the limb to become purple, black, and even tissue ulceration and necrosis.

The term "Ginkgo biloba extract" refers to the extract obtained by extracting Ginkgo biloba leaves, including active ingredients such as flavonoid glycosides (flavonglycosides) and ginkgolides (ginkgolides).

The term "extraction" refers to the use of different components in a mixture that have different Solubility, a method to separate out specific components in a mixture. Extraction can be divided into two ways, namely liquid-liquid extraction and solid-liquid extraction, which are ways of separating specific components from liquid mixtures and solid mixtures, respectively.

The term "flavonoid glycosides (flavonglycosides)", also known as "flavonoids (flavonoids)", refers to a component in Ginkgo biloba extract. Current research indicates that flavonoid glycosides have antioxidant and free radical scavenging properties. Function.

The term "ginkgolides" refers to a component of Ginkgo biloba extract. Current research indicates that ginkgolides are antagonists of platelet-activating factor (PAF), which can promote platelet activation and aggregation. . In addition, ginkgolide is also used to treat cerebrovascular disease and migraine.

As used herein, "disease" in an individual's state of health refers to the inability of the individual to maintain homeostasis, and if the disease does not improve, the individual's health continues to deteriorate.

As used in this specification, the terms "treating", "treating" and "method of treatment" refer to reducing the frequency or severity of symptoms of a disease or disorder experienced by an individual by administering an agent or pharmaceutical composition to the individual.

As used in this specification, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, which is the Ginkgo biloba extract, or its salts, solvates, hydrates, Prodrugs, enantiomers, nonenantiomers or geometric isomers, the Ginkgo biloba extract retains its biological activity or properties and is relatively non-toxic. That is, the material can be administered to an individual without causing undesired biological effects or interacting in a detrimental manner with any ingredient contained in the composition.

"Pharmaceutically acceptable carrier" as used in this specification includes salts, materials, compositions or carriers, such as fillers, diluents, excipients or encapsulating materials, which allow the Ginkgo biloba extract of the present invention Apply to subjects and allow Ginkgo biloba extract to perform its intended function. Each salt or carrier must be compatible with the other ingredients of the formulation, including the Ginkgo biloba extract useful in the present invention, and not injurious to the subject. Examples of materials that can be used as carriers include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate vegan; powdered tragacanth; malt; gelatin; talc; excipients such as Butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene diols; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; diluents; granulating agents; lubricants; binders; disintegrating agents; Wetting agents; emulsifiers; colorants; release agents; coating agents; fragrances; preservatives; antioxidants; plasticizers; gelling agents; thickeners; hardeners; styling agents; surfactants; humectants ; carriers; stabilizers; and other non-toxic compatible substances used in the formulation, or any combination thereof.

The pharmaceutical compositions of the methods of the present invention are suitable for topical or transdermal routes of administration. Suitable pharmaceutical compositions are in the form of, for example, but not limited to, gels, emulsions, transdermal patches, creams, pastes.

Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid formulations, such as liniments, lotions, oil-in-water or water-in-oil emulsions, such as creams, ointments, or ointments. Formulations for topical application may, for example, contain from about 1% to about 10% (w/w) active ingredient, although the concentration of active ingredient may be as high as the limit of solubility of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

Carriers in gels, emulsions, transdermal patches, creams, ointments of pharmaceutical compositions for topical or transdermal administration can be, for example, but not limited to, mineral oil, propylene glycol, polyoxypropylene, emulsifying wax, glycerin, polyethylene Glycol, fatty alcohol, fatty ether, fatty acid ester, vegetable oil, silicone oil, petrolatum, lanolin, beeswax, hyaluronic acid, polyacrylic acid, polyvinylpyrrolidone, gelatin, dextrin, polysaccharide, polyacrylamide, Polyvinyl alcohol, polyvinyl acetate, hydroxypropyl methylcellulose or carboxypropyl methylcellulose.

Pharmaceutical compositions for topical administration may optionally be combined with other ingredients such as adjuvants, antioxidants, chelating agents, surfactants, foaming agents, wetting agents, emulsifiers, viscosity enhancing agents, buffers, preservatives, and the like. In other embodiments, a penetration or penetration enhancer is included in the composition and is effective to improve transdermal penetration of the active ingredient into and through the stratum corneum relative to a composition lacking a penetration enhancer. Various penetration enhancers are known to those skilled in the art and include oleic acid, oleyl alcohol, ethoxydiethylene glycol, laurozone, alkenyl carboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl -2-pyrrolidone. In another embodiment, the composition may further comprise a solubilizer, the function of which is to increase the degree of disorder in the structure of the stratum corneum, thereby increasing transport across the stratum corneum. Various solubilizers are known to those skilled in the art such as isopropanol, propylene glycol or sodium xylene sulfonate.

The formulation of the pharmaceutical composition described in this specification can be prepared by any method known in the field of pharmacology and pharmacy or developed in the future. Generally, such methods of preparation include the steps of bringing into association the active ingredient with a carrier or one or more other accessory ingredients and then - if desired or feasible - forming or packaging the product in the desired single-dose or multi-dose units .

As used in this specification, "patient", "individual" and "subject" are used interchangeably and refer to a human or a non-human mammal. Non-human mammals include, for example, domestic animals and pets such as sheep, cattle, pigs, canines, felines, and murine mammals. Preferably, the patient is a human.

The term "neonatal" refers to humans within 28 days of birth. The term "infant" refers to a human between 28 days after birth and 1 year of age. The term "infant" refers to a human between 1 and 3 years of age. The term "preterm infant" specifically refers to a newborn born at 20 weeks of gestation, but less than 37 weeks.

The "dose" used in this specification means the amount of Ginkgo biloba extract that can promote blood circulation. In the gel, cream or ointment of the present invention, the dosage of Ginkgo biloba extract is between 0.01 mg/ml and 5 mg/ml. Preferably, the dosage of Ginkgo biloba extract is between 0.05 mg/ml and 3 mg/ml. Preferably, the dosage of Ginkgo biloba extract is between 0.08 mg/ml and 2 mg/ml. In the transdermal patch of the present invention, the dosage of Ginkgo biloba extract is between 0.01 mg/cm 2 to 5 mg/cm 2 . Preferably, the dosage of Ginkgo biloba extract is between 0.05 mg/cm 2 to 3 mg/cm 2 . Preferably, the dosage of Ginkgo biloba extract is between 0.08 mg/cm 2 and 2 mg/cm 2 .

Ranges: Throughout this disclosure, various embodiments of this disclosure may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as limiting the scope of the invention. Accordingly, the description of a range should be considered to specifically disclose all possible subranges as well as individual numerical values within that range. For example, a description of a range from 1 to 6 should be considered to have specific disclosed subranges, such as from 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and in Single and partial numbers within the range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. The foregoing rules apply regardless of the span of the scope.

A pharmaceutical composition for treating ischemia according to the present invention is used for a patient suffering from ischemia. The pharmaceutical composition comprises a Ginkgo biloba extract and a pharmaceutically acceptable carrier, wherein the dosage form of the pharmaceutical composition is: Gel, transdermal patch, cream or ointment. In this embodiment, you can Extracting or weighing a dose of Ginkgo biloba extract, adding a pharmaceutically acceptable carrier to prepare a pharmaceutical composition, and then applying it to the ischemic part of the patient to achieve the effect of promoting blood circulation in the part, and then used for Treat ischemia.

In addition, the dosage forms included in the pharmaceutical composition of the present invention are gels, transdermal patches, creams or ointments. In this embodiment, when the dosage form of the pharmaceutical composition is gel, cream or ointment, the dosage of Ginkgo biloba extract is between 0.01 mg/ml and 5 mg/ml, preferably, the dosage of Ginkgo biloba extract Between 0.05 mg/ml and 3 mg/ml. Preferably, the dosage of Ginkgo biloba extract is between 0.08 mg/ml and 2 mg/ml. In this embodiment, when the dosage form of the pharmaceutical composition is a transdermal patch, the dosage of Ginkgo biloba extract is between 0.01 mg/cm² and 5 mg/cm², preferably, the dosage of Ginkgo biloba extract is between 0.01 mg/cm² and 5 mg/cm². Between 0.05 mg/cm2 and 3 mg/cm2. Preferably, the dosage of Ginkgo biloba extract is between 0.08 mg/cm 2 and 2 mg/cm 2 . Of course, the dosage of Ginkgo biloba extract can be any value and range encompassed between any two values in the aforementioned range, and may vary with the carrier on the treatment, the route of administration or the individual in need and their physiological conditions varies from one to another.

In this embodiment, the Ginkgo biloba extract is extracted from Ginkgo biloba leaves, and includes more than 20% of flavonoid glycosides (flavonglycosides) and more than 5% of ginkgolides. Preferably, the ginkgo extract includes more than 24% flavonoid glycosides and more than 6% ginkgolides.

In this embodiment, the pharmaceutically acceptable carrier is mineral oil, propylene glycol, polyoxypropylene, emulsifying wax, glycerin, polyethylene glycol, fatty alcohol, fatty ether, fatty acid ester, vegetable oil, silicone oil, petrolatum , lanolin, beeswax, hyaluronic acid, polyacrylic acid, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl methylcellulose or carboxypropyl methyl base cellulose. Preferably, the pharmaceutically acceptable carrier is petrolatum.

In this embodiment, the ischemia is extremity ischemia, also known as extremity ischemia or terminal ischemia, such as but not limited to chronic extremity ischemia or acute extremity ischemia.

In this embodiment, the patient is a neonate, infant or toddler. Preferably, the patient is a preterm infant among neonates.

The present invention also provides the use of a Ginkgo biloba extract for preparing a medicinal composition for treating ischemia. Additionally, the present invention provides a method for treating ischemia comprising adding a pharmaceutical The composition is applied to the affected part of a patient suffering from ischemia, the pharmaceutical composition comprises a Ginkgo biloba extract and a pharmaceutically acceptable carrier, and the pharmaceutical composition is in the form of a gel, a transdermal patch, a cream or an ointment , the ischemia system is extremity ischemia, and the patient is a premature infant. However, the dosage, type of carrier, and other properties of the pharmaceutical composition are substantially the same as those of the pharmaceutical composition described above, which can be referred to above, and will not be repeated here.

Continuing from the above, according to the pharmaceutical composition of the present invention and its preparation application, it can directly act on the ischemic tissue to promote the blood circulation of the local tissue, so as to avoid numbness, pain and even purplishness of the local tissue due to ischemia. , blackening, ulceration or necrosis, so as to achieve the effect of treating ischemia, and at the same time avoid the side effects caused by the drug acting on other tissues.

The following experimental examples are used to illustrate the use and pharmaceutical composition of the present invention, which provide significant efficacy in improving the therapeutic effect of extremity ischemia.

Experimental Example 1: Preparation of a pharmaceutical composition.

Mix 0.08 mg to 2 mg of Ginkgo biloba extract (trade name Ginkgo biloba film-coated tablets, Yongxin Pharmaceutical Industry Co., Ltd.) with 1 ml of sterile gel (patient lubricant (sterilized), CEYOTEK Patient lubricant (Sterile) ), Xuyu Technology Co., Ltd.) and mixed to prepare a pharmaceutical composition with a ginkgo extract dosage of 0.08 mg/ml to 2 mg/ml, which was used in the experiments of the subsequent experimental example 2.

Experimental example 2: Ginkgo biloba extract can improve the symptoms of acral ischemia in premature infants.

participating patients

The patients were from patients with preterm infants who suffered from extremity ischemia treated by Shin Kong Wu Huoshi Memorial Hospital from June 2018 to December 2018. The preterm infants in this experiment were all signed by their parents or legal representatives with written informed consent approved by the Institutional Review Board (IRB) of the hospital.

Therapeutic method using the pharmaceutical composition of the present invention

The pharmaceutical composition prepared in Experimental Example 1 was taken and applied to the ischemic sites (affected areas) of Patient 1, Patient 2, and Patient 3. The thickness of the application is about 1mm, and the application area varies according to the area of the affected area, and the affected area needs to be completely covered. After application, cover with a layer of gauze and apply a warm compress for 30 minutes to allow the medicinal composition to be absorbed by the affected area. Subsequently, the gauze was removed and the pharmaceutical composition was applied, covered with a new layer of gauze and left for 30 minutes (without warm compress). The above steps were one course of treatment. Repeat the above course of treatment: apply the medicinal composition, cover with a layer of gauze and apply a warm compress for 30 minutes, then remove the gauze and apply the medicinal composition, then cover with a new gauze and let it stand for 30 minutes (without warm compress) until the affected area is deficient. The time was recorded when the blood condition improved significantly, after which the treatment was continued until complete cure.

Please refer to Table 1 for an explanation of Patient 1's treatment status. As shown in Table 1, patient 1 developed ischemic symptoms on the second day after birth, and symptom improvement was observed after 3 hours of treatment with the pharmaceutical composition of the present invention (3 hours after treatment, that is, 3 courses of treatment). In addition, the time for complete recovery of ischemic symptoms of patient 1 was 4 hours (after 4 hours of treatment, ie, 4 courses of treatment).

Please refer again to Table 1 to explain the treatment status of Patient 2. As shown in Table 1, patient 2 developed ischemic symptoms on the second day after birth, and symptom improvement was observed after 3.2 hours of treatment with the pharmaceutical composition of the present invention (after 3 hours of treatment, i.e., 3 courses of treatment). In addition, the time for complete recovery of the ischemic symptoms of patient 2 was 4 hours (after 4 hours of treatment, that is, 4 courses of treatment).

Please refer again to Table 1 to explain the treatment status of patient 3. As shown in Table 1, patient 3 developed ischemic symptoms on the first day after birth, and symptom improvement was observed after 10 days of treatment with the pharmaceutical composition of the present invention (after 10 days of treatment). In addition, patient 3 was completely cured of ischemic symptoms The time period was 24 days (24 days after treatment).

According to the results of the above experimental examples, the pharmaceutical compositions of the embodiments of the present invention can improve or even cure the ischemia of the extremities (toes) of premature infants. In particular, although the aforementioned experimental example takes the treatment of extremity ischemia in premature infants as an example to illustrate, however, the pharmaceutical composition of the present invention and its preparation application can also be used for neonates, infants or young children of non-premature infants. Not limited to this, and the treated parts can also be used for other parts, such as but not limited to fingers, arms, calves, thighs, etc. In addition, although the carrier used in the pharmaceutical composition of the above experimental example is illustrated by taking gel as an example, the pharmaceutical composition can also include the carrier described in other parts of this document, which is not limited here.

To sum up, the pharmaceutical composition of the present invention and its preparation application can directly act on the ischemic tissue to promote the blood circulation of the local tissue, so as to avoid numbness, pain, and even purplish, Blackening, festering or necrosis, so as to achieve the effect of treating ischemia, and at the same time avoid the side effects caused by the drug acting on other tissues.

The above description is exemplary only, not limiting. Any equivalent modifications or changes that do not depart from the spirit and scope of the present invention shall be included in the appended patent application scope.

Claims (3)

Use of a ginkgo extract for preparing a medicinal composition for treating ischemia, the medicinal composition is used for a patient suffering from ischemia, and the medicinal composition comprises a ginkgo extract and a pharmaceutically acceptable carrier , wherein the dosage form of the pharmaceutical composition is a gel, a transdermal patch, a cream or an ointment, the patient is a newborn, an infant or a young child, the ischemic site has no wound, and the dosage of the ginkgo extract is between Between 0.01 mg/ml and 5 mg/ml or between 0.01 mg/cm 2 and 5 mg/cm 2 . The use as described in item 1 of the application scope, wherein the ginkgo extract is extracted from ginkgo leaves, and comprises more than 20% of flavonoid glycosides and more than 5% of ginkgolide. The use as described in item 1 of the scope of the application, wherein the pharmaceutically acceptable carrier is mineral oil, propylene glycol, polyoxypropylene, emulsifying wax, glycerin, polyethylene glycol, fatty alcohol, fatty ether, fatty acid ester, Vegetable oil, silicone oil, petrolatum, lanolin, beeswax, hyaluronic acid, polyacrylic acid, polyvinylpyrrolidone, gelatin, dextrin, polysaccharide, polyacrylamide, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl methyl alcohol cellulose or carboxypropyl methylcellulose.