Anti-vascular disease and antitumor pharmaceutical composition and use thereof

Abstract

An anti-vascular diseases and antitumor pharmaceutical composition is provided in the present invention, and it includes effective ingredients including bleomycin antitumor antibiotic, adrenal glucocorticoid, epinephrine or pharmaceutically acceptable salts thereof in a weight ratio of (1-8):(2-5):(0.00005-0.001). The pharmaceutical composition provided can be used for treatment of vascular diseases and tumors.

Claims

1. An anti-vascular malformation pharmaceutical composition, wherein the pharmaceutical composition comprises effective ingredients comprising pingyangmycin, dexamethasone and epinephrine or pharmaceutically acceptable salts thereof in a weight ratio of 7:4.3755:0.00035.

2. The pharmaceutical composition according to claim 1, wherein a total weight of the pingyangmycin, dexamethasone, and epinephrine accounts for 20%-90% of the weight of the pharmaceutical composition.

3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable auxiliary.

4. The pharmaceutical composition according to claim 3, wherein the pharmaceutically acceptable auxiliary comprises at least one of a pH regulator and mannitol.

5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is in a dosage form of injection, freeze-dried powder, or microspheres.

6. The pharmaceutical composition according to claim 5, wherein the microspheres are albumin microspheres, magnetic nano-microspheres, control-released magnetic nano-microspheres, or cellular targeted magnetic nano-microspheres.

7. A method for treating vascular malformations, comprising the step of: preparing a medication comprising the pharmaceutical composition of claim 1; administering the medication to a patient suffering from the vascular malformations.

8. The method for treating vascular malformations, comprising the step of: preparing a medicine comprising the pharmaceutical composition of claim 2; administering the medication to a patient suffering from the vascular malformations.

9. The method for treating vascular malformations, comprising the step of: preparing a medicine comprising the pharmaceutical composition of claim 3; administering the medication to a patient suffering from the vascular malformations.

10. The method for treating vascular malformations, comprising the step of: preparing a medicine comprising the pharmaceutical composition of claim 4; administering the medication to a patient suffering from the vascular malformations.

11. The method for treating vascular malformations, comprising the step of: preparing a medicine comprising the pharmaceutical composition of claim 5; administering the medication to a patient suffering from the vascular malformations.

12. The method for treating vascular malformations, comprising the step of: preparing a medicine comprising the pharmaceutical composition of claim 6; administering the medication to a patient suffering from the vascular malformations.

Description

BRIEF DESCRIPTION

(1) Some of the embodiments will be described in detail, with reference to the following figures, wherein like designations denote like members, wherein:

(2) FIG. 1 shows a bottle filled with prepared compound pingyangmycin injection product of embodiments of the present invention;

(3) FIGS. 2A and 2B shows the effect before/after the injection of the product of embodiments of the present invention applied to treat lingual venous malformation;

(4) FIGS. 3A and 3B shows the effect before/after the injection of the product of embodiments of the present invention applied to treat lower-lip venous malformation;

(5) FIGS. 4A-4D, wherein FIGS. 4A and 4C are the frontal view and lateral view of the right cheek of a patient suffered from mixed venous-lymphatic malformation respectively; FIGS. 4B and 4D are the frontal view and lateral view of the right cheek of a patient, after the treatment with the product of embodiments of the present invention.

DETAILED DESCRIPTION

(6) Embodiments of the present invention will be further explained with reference to embodiments.

EXAMPLE 1

Preparation of Compound Pingyangmycin Injection

(7) The preparation is conducted as following process.

(8) Weight pingyangmycin, dexamethasone and epinephrine, dissolve the pingyangmycin and dexamethasone in water and dissolve the epinephrine in hydrochloric acid, and subsequently mix them to obtain a mixed aqueous solution; adjust the pH to 4.0-6.5 with hydrochloric acid and sodium hydroxide to obtain a compound pingyangmycin injection. The compound pingyangmycin injection comprises pingyangmycin, dexamethasone and epinephrine in a weight ratio of 2:1:0.0001, and the total weight of these three ingredients accounts for 0.3 wt. % of the weight of the obtained injection. The prepared compound pingyangmycin injection can be used for the direct injection of focal tumor cavity directly, or can be injected after being diluted to the required concentration with normal saline or glucose injection as medically indicated.

EXAMPLE 2

Preparation of Compound Pingyangmycin Injection

(9) The pingyangmycin freeze-dried powder-injection (purchased from Tianjin Taihe Pharmaceutical Co., Ltd) is used as bottle A, and is reserved for later use; mix the epinephrine injection (purchased from Beijing YOKON Pharmaceutical Co., Ltd) and the dexamethasone injection (purchased from Henan Runhong Pharmaceutical Co., Ltd) in a proper proportion to obtain a bottle B, which is called as epinephrine and dexamethasone injection, reserve it for later use; mix the pingyangmycin freeze-dried powder-injection and dexamethasone injection containing epinephrine to obtain a compound pingyangmycin injection. The compound pingyangmycin injection comprises pingyangmycin, dexamethasone and epinephrine in a weight ratio of 2:1.25:0.0001, and the total weight of these three ingredients accounts for 0.298 wt. % of the weight of the obtained compound pingyangmycin injection. FIG. 1 shows the appearance figure of a bottle filled with prepared injection. The prepared compound pingyangmycin injection can be used for the direct injection of focal tumor cavity directly, or can be injected after being diluted to the required concentration with normal saline or glucose injection as medically indicated. The preparation method in example 2 could substitute that in example 1.

EXAMPLE 3

Preparation of Compound Pingyangmycin Freeze-Dried Powder-Injection

(10) The preparation is conducted as follows.

(11) Weight pingyangmycin, dexamethasone and epinephrine, dissolve the lidocaine pingyangmycin and dexamethasone in water and dissolve the epinephrine in hydrochloric acid, and subsequently mix them to obtain a mixed aqueous solution; adjust the pH to 4.0-6.5 with hydrochloric acid and sodium hydroxide, and perform freeze-drying after dispensing to obtain a compound pingyangmycin freeze-dried powder-injection. The compound pingyangmycin freeze-dried powder-injection comprises pingyangmycin, dexamethasone and epinephrine in a weight ratio of 8:5:0.0001, and the total weight of these three ingredients accounts for 85 wt. % of the weight of the compound pingyangmycin freeze-dried powder-injection. The freeze-dried powder-injection is dispensed into bottles, and 8 mg pingyangmycin, 5 mg dexamethasone and 0.0001 mg epinephrine are contained in each bottle. When used, the compound pingyangmycin freeze-dried powder-injection is dissolved with normal saline or glucose injection, to obtain a compound pingyangmycin injection.

EXAMPLE 4

Preparation of Compound Pingyangmycinalbumin Microspheres

(12) The preparation is conducted as following process.

(13) 1) Weight pingyangmycin, dexamethasone and epinephrine, then dissolve the lidocaine pingyangmycin and dexamethasone in water and dissolve the epinephrine in hydrochloric acid, and subsequently mix them to obtain a compound pingyangmycin solution.

(14) 2) Prepare compound pingyangmycin albumin microspheres through emulsifying-curing method: well mixing the obtained compound pingyangmycin solution of step 1) with 20 wt. % human albumin solution, cure the mixture with glutaraldehyde after ultrasonic homogenization, and then wash repeatedly, finally dry and collect it to obtain compound pingyangmycin albumin microspheres. The compound pingyangmycin albumin microspheres comprise pingyangmycin, dexamethasone and epinephrine in a weight ratio of 8:5:0.0001, and the total weight of these three ingredients accounts for 60% of the weight of the compound pingyangmycin albumin microspheres. The compound pingyangmycin albumin microspheres are dispensed into bottles, and 8 mg pingyangmycin, 5 mg dexamethasone and 0.0001 mg epinephrine are contained in each bottle.

EXAMPLE 5

Preparation of Compound Pingyangmycin Magnetic Nano-Microspheres

(15) The preparation is conducted as following process.

(16) Dissolve the sodium alginate sealing agent and silica-wrapped magnetic nano-microspheres in an aqueous solution in a proper proportion, stir and add the compound pingyangmycin solution prepared as the process of step 1) in example 4. Then add liquid paraffin containing Span85 slowly, place it in an ice bath after emulsifying, add formaldehyde and isopropanol successively, and filtrate after stirring, then wash them with anhydrous ether and acetone, finally dry and sieve them to obtain the compound pingyangmycin magnetic nano-microspheres. The compound pingyangmycin magnetic nano-microspheres formulation comprises pingyangmycin, dexamethasone and epinephrine in a weight ratio of 8:2:0.0001, and the total weight of these three ingredients accounts for 30% of the weight of the compound pingyangmycin magnetic nano-microspheres formulation. The microspheres formulations are dispensed into bottles, and 8 mg pingyangmycin, 2 mg dexamethasone and 0.0001 mg epinephrine are contained in each bottle.

EXAMPLE 6

Preparation of Compound Pingyangmycin Control-Released Magneticnano-Microspheres Formulation

(17) The preparation is conducted as following process.

(18) 1) Prepare compound pingyangmycin solution according to the process of step 1) in example 4;

(19) 2) Add dichloromethane solution in which carbon-coated iron (Fe@C) nano-microspheres and poly lactide-glycolide acid (PLGA) have been dissolved in the pre-emulsifying reactor, then add the obtained compound pingyangmycin solution in step 1) in the pre-emulsifying reactor, stir at a high speed to obtain a water-in-oil compound pingyangmycin pre-emulsion, which is subsequently added slowly into the PVA aqueous solution and stirred to form a water-in-oil-in-water (W/O/W) multiple emulsion, then slow down the stirring rate and obtain the compound pingyangmycin PLGA microspheres after gradual curing, and dry the microspheres through freeze-drying method after washing to obtain the compound pingyangmycin control-released magnetic nano-micropheres formulation. The compound pingyangmycin control-released magnetic nano-micropheres formulation comprises pingyangmycin, dexamethasone and epinephrine in a weight ratio of 8:5:0.0001, and the total weight of these three ingredients accounts for 28% of the weight of the compound pingyangmycin control-released magnetic nano-microspheres formulation. The microspheres formulations are dispensed into bottles, and 8 mg pingyangmycin, 5 mg dexamethasone and 0.0001 mg epinephrine are contained in each bottle.

EXAMPLE 7

Preparation of Compound Pingyangmycin Targeted Magnetic Nano-Microspheres Formulation

(20) The preparation is conducted as following process.

(21) Prepare compound pingyangmycin magnetic nano-microspheres according to the process of example 5; mix the dolichos bifows agglutinin (DBA) solution with the compound pingyangmycin magnetic nano-micropheres before drying, to make the dolichos bifows agglutinin (DBA) adhere to the surface of nano-microsphere, dry them through freeze-drying method after washing to obtain the compound pingyangmycin targeted magnetic nano-micropheres formulation. The compound pingyangmycin targeted magnetic nano-micropheres formulation comprises pingyangmycin, dexamethasone and epinephrine in a weight ratio of 8:2:0.0001, and the total weight of these three ingredients accounts for 28% of the weight of the compound pingyangmycin targeted magneticnano-microphere formulation. The microspheres formulations are dispensed into bottles, and each bottle has 8 mg pingyangmycin, 2 mg dexamethasone, 0.0001 mg epinephrine.

APPLICATION EXAMPLE

(22) The pharmaceutical composition of embodiments of the present invention is well effective in treatment of vascular diseases and tumors, and several typical application examples are illustrated as follows.

Application Example 1

Usage of the Pharmaceutical Composition of Embodiments of the Present Invention in Treatment of Tongue-Tip Venous Malformation

(23) WANG was found venous malformation in the tongue-tip, shown as a livid swelling, before treatment. Compound pingyangmycin injection was used for treatment. Before injection, dilute the compound pingyangnycin injection with normal saline to obtain an injection containing 1 mg pingyangmycin, 0.625 mg dexamethasone and 0.00005 mg epinephrine for every 0.5 ml injection. Perform tumor-intracavity injection with 0.5 ml diluted injection, and repeat the injection after two weeks. As a result, the livid swelling in tongue-tip of the patient almost disappears, and the photographs of tongue-tip of the patient before and after the injection are shown in FIGS. 2A and 2B respectively. During the treatment, no severe adverse reaction, such as anaphylactic shock, hard breath and hyperpyrexia, etc., occurred for the patient.

(24) The compound pingyangmycin injection used in the example can be prepared according to the process of example 2.

Application Example 2

Usage of the Pharmaceutical Composition of Embodiments of the Present Invention in Treatment of Venous Malformation in Lower Right Lip

(25) LI was found venous malformation in the lower right lip, shown as a livid swelling and hypertrophy, before treatment. Compound pingyangmycin injection was used for treatment. Before injection, dilute the compound pingyangnycin injection with normal saline to obtain an injection containing 7 mg pingyangmycin, 4.3755 mg dexamethasone and 0.00035 mg epinephrine for every 3.5 ml injection. Perform tumor-intracavity injection with 3.5 ml diluted injection, and repeat the injection after two weeks. As a result, the livid swelling in tongue-tip of the patient almost disappears, both sides of the lower lip are nearly symmetrical, and the photographs of lips of patient before and after the injection are shown in FIGS. 3A and 3B respectively. During the treatment, no severe adverse reaction, such as anaphylactic shock, hard breath and hyperpyrexia, etc., occurred for the patient.

(26) The compound pingyangmycin injection used in the example can be prepared according to the process of example 2.

Application Example 3

Usage of the Pharmaceutical Composition of Embodiments of the Present Invention in Treatment of Mixed Vein and Lymphatic Malformation in Cheek

(27) ZHOU was found obvious hypertrophy in the right cheek and livid venous malformation on the surface of skin, before treatment. Compound pingyangmycin injection was used for treatment. Before injection, dilute the compound pingyangnycin injection to obtain an injection containing 8 mg pingyangmycin, 5 mg dexamethasone and 0.002 mg epinephrine for 4 ml injection in each bottle. Perform tumor-intracavity injection with 4 ml diluted injection, and repeat the injection after four weeks. As a result, the hypertrophy in right cheek of the patient is significantly reduced and the livid area in the skin almost disappears. Front and lateral photographs of mixed venin and lymphatic malformation in right cheek of the patient before treatment are shown in FIGS. 4A and 4C, and the front and lateral photographs of right cheek are shown in FIGS. 4B and 4D. During the treatment, no severe adverse reaction, such as anaphylactic shock, hard breath and hyperpyrexia, etc., occurred for the patient.

(28) The compound pingyangmycin injection used in the example can be prepared according to the process of example 1.

Application Example 4

Usage of the Pharmaceutical Composition of Embodiments of the Present Invention in Treatment of Maxillary Gingiva Squamous-Cell Carcinoma

(29) ZHU was found swelling in maxillary gingiva before treatment. Compound pingyangmycin injection was used for treatment. Before injection, dilute the compound pingyangnycin injection with normal saline to obtain an injection containing 8 mg pingyangmycin, 10 mg dexamethasone and 0.0001 mg epinephrine for every 8 ml injection. During treatment, perform tumor-intracavity injection with 8 ml diluted injection. After treatment, the swelling in maxillary gingiva of the patient is relived. During the treatment, no severe adverse reaction, such as anaphylactic shock, hard breath and hyperpyrexia, etc., occurred for the patient.

(30) The compound pingyangmycin injection used in the example can be prepared according to the process of example 1.

(31) The compound pingyangmycin injection used in above application examples may also be compound formulations in other dosage forms, such as compound pingyangmycin injection freeze-dried powder-injection, or microspheres, and the dilution and dissolution should be conducted before usage.

(32) Substances in above examples were purchased from the market, if no special explanation was made. Those contents not been specially explained in the preparation method are technologies known for one skilled in the art or can be obtained from prior art.

(33) Although the present invention has been disclosed in the form of preferred embodiments and variations thereon, it will be understood that numerous additional modifications and variations could be made thereto without departing from the scope of the invention.

(34) For the sake of clarity, it is to be understood that the use of a or an throughout this application does not exclude a plurality, and comprising does not exclude other steps or elements.