CN117582447A - Medicament prepared from organogermanium compound and glucosamine compound and use thereof - Google Patents
Medicament prepared from organogermanium compound and glucosamine compound and use thereof Download PDFInfo
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- CN117582447A CN117582447A CN202311006455.XA CN202311006455A CN117582447A CN 117582447 A CN117582447 A CN 117582447A CN 202311006455 A CN202311006455 A CN 202311006455A CN 117582447 A CN117582447 A CN 117582447A
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- germanium
- compound
- chitosan
- tricyclic
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- 239000003814 drug Substances 0.000 title claims abstract description 111
- -1 organogermanium compound Chemical class 0.000 title claims abstract description 72
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 229960002442 glucosamine Drugs 0.000 title claims abstract description 29
- 229940079593 drug Drugs 0.000 claims abstract description 53
- 230000029663 wound healing Effects 0.000 claims abstract description 43
- 150000002291 germanium compounds Chemical class 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 229920001661 Chitosan Polymers 0.000 claims description 115
- 208000027418 Wounds and injury Diseases 0.000 claims description 75
- 206010052428 Wound Diseases 0.000 claims description 74
- XEABSBMNTNXEJM-UHFFFAOYSA-N propagermanium Chemical compound OC(=O)CC[Ge](=O)O[Ge](=O)CCC(O)=O XEABSBMNTNXEJM-UHFFFAOYSA-N 0.000 claims description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
- 230000000694 effects Effects 0.000 claims description 36
- 229910052732 germanium Inorganic materials 0.000 claims description 34
- 239000000243 solution Substances 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 125000000082 organogermanium group Chemical group 0.000 claims description 24
- 239000000843 powder Substances 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 125000003277 amino group Chemical group 0.000 claims description 15
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 15
- 230000006196 deacetylation Effects 0.000 claims description 15
- 238000003381 deacetylation reaction Methods 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 14
- QAIPRVGONGVQAS-DUXPYHPUSA-N caffeic acid Natural products OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 claims description 12
- 230000005588 protonation Effects 0.000 claims description 12
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 claims description 11
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
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- ACEAELOMUCBPJP-UHFFFAOYSA-N (E)-3,4,5-trihydroxycinnamic acid Natural products OC(=O)C=CC1=CC(O)=C(O)C(O)=C1 ACEAELOMUCBPJP-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 108010009583 Transforming Growth Factors Proteins 0.000 claims description 8
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- 235000004883 caffeic acid Nutrition 0.000 claims description 8
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- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 claims description 8
- PKCYYRXPGMHIPO-UHFFFAOYSA-N 4-[[3-carboxypropyl(oxo)germyl]oxy-oxogermyl]butanoic acid Chemical group OC(=O)CCC[Ge](=O)O[Ge](=O)CCCC(O)=O PKCYYRXPGMHIPO-UHFFFAOYSA-N 0.000 claims description 7
- SHIBUSVCBKYBNB-UHFFFAOYSA-N C12=CC=C(N1)C=C1C=CC(=N1)C=C1C=CC(N1)=CC=1C=CC(N1)=C2.[Ge] Chemical class C12=CC=C(N1)C=C1C=CC(=N1)C=C1C=CC(N1)=CC=1C=CC(N1)=C2.[Ge] SHIBUSVCBKYBNB-UHFFFAOYSA-N 0.000 claims description 7
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- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
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- WBYWAXJHAXSJNI-UHFFFAOYSA-N cinnamic acid group Chemical group C(C=CC1=CC=CC=C1)(=O)O WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 claims description 4
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Diabetes (AREA)
- Hematology (AREA)
- Dermatology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A medicament prepared from an organogermanium compound and a glucosamine compound and uses thereof, characterized by comprising: (1) The high water-soluble salt medicine prepared from the organic germanium compound and the glucosamine compound is suitable for being prepared into various favorable medicinal formulations; (2) The salt-type drug maintains the biochemical, pharmacological and medical properties of its components, and has excellent efficacy in many medical uses including, but not limited to, wound healing, since the pharmacological properties of its components have a complementary effect in medical treatment.
Description
Technical Field
The invention relates to a medicine prepared from an organic germanium compound and a glucosamine compound and application thereof, in particular to a medicine which has the effects of easing pain, resisting inflammation, resisting oxidation, resisting hypoxia, regulating immunity, resisting virus, inhibiting bacteria, coagulating, accelerating cell proliferation and the like, can stimulate organisms to secrete interferon and derive transforming growth factors, and medical application thereof in promoting healing of various wounds.
Background
The study of biochemical activities and medical applications of organogermanium compounds has been carried out for decades, some of which have been found to have analgesic (analgesic action), anti-inflammatory (anti-inflammatory action), antioxidant (antioxidant effect) and antihypoxic (antihyproxic effect), immunomodulating (immunomodulating action), antiviral (anti-viral action) (v.g. lakhtin et al, "Synthesis and application of organogermanium compounds", polymer Science Series D, vol.4, iss.3, pp 221-227,2011-07-01;D.W.Niesel,C.B.Hess,Y.J.Cho,K.D.Klimpel and G.R.Klimpel,Infection and Immunity,June 1986,Vol.52,No.3,pp 828-833;L.G.Menchikov1and M.A.Ignatenko, "Biological Activity of Organogermanium Compounds-a Review", pharmaceutical Chemistry Journal, vol.46, no.11, february, 2013), among which bis-carboxyethyl germanium sesquioxide (bis (2-carboxzylgermanium) sequioxide, ge-132) and derivatives thereof have been most widely and intensively studied. Bis-carboxyethylgermanium sesquioxide (Ge-132) and its derivatives have been widely studied for use in anticancer, antihypertensive, liver disease prevention, antirheumatic (Pronai, L.and Arimori, S., "Decreased Plasma Superoxide Scavenging Activity in Immunological Disorder-Carboxyethylgermanium sesquioxide (Ge-132) as a Promoter of Prednisolone", biotherapy,1992,4,1-8), anti-cataract (Unaka, N.J. et al, 1995, "Effect of Germanium-132on Galactose Cataracts and Glycation in Rats", experimental Eye Research,61, 155-164), osteoporosis inhibition, and inflammation treatment, etc., and have also been applied to the preparation of Make up cosmetics and nutritional agents, etc. While the latest studies (Robin A. Reddeman et al, "A Toxicological Evaluation of Germanium Sesquioxide (Organic Germanium)", hindawi, journal of Toxicology, vol.2020, article ID 6275525, 17 pages) have determined that Ge-132 has a degree of no visible Adverse Effect (NOAEL: non-Observable-advverse-Effect Level) of 2000 mg/kg body weight/day, is a very low toxic substance, but may suffer from germanium dioxide (GeO 2 ) The pollution causes serious kidney poisoning, so that the pollution caused by germanium dioxide is avoided, and the method becomes an important subject for preparing the organogermanium medicament. The preparation of organogermanium in liquid form is an effective method for eliminating the contamination of solid germanium dioxide and the limited application of organogermanium due to low water solubility.
In addition to organogermanium sesquioxides and derivatives thereof, other types OF organogermanium compounds, including germane compounds (gemanes), heteronitrogen germanium tricyclic compounds (gemarans), helical germanium compounds (spirogermanium compounds), germanium porphyrin compounds (germanium porphyrines), and dicyclopentadienyl germanium compounds (gemanacenes), and the like, are also disclosed as having similar biological activities as bis-carboxyethyl germanium sesquioxides (l.g. menchikov and m.a. ignateko, "MOLECULAR-BIOLOGICAL PROBLEMS OF DRUG DESIGN AND MECHANISM OF DRUG ACTION: biological Activity OF Organogermanium Compounds (a Review)", pharmaceutical Chemistry Journal, vol.46, no.11, february, 2013).
Many studies have also demonstrated that organogermanium compounds are capable of stimulating gamma interferon secretion in vivo and derivatizing transforming growth factors (transforming growth factor, TGF), which should be an effective way to promote wound healing. Wounds are also common wounds in the body, in addition to skin wounds such as wounds, lacerations, abrasions, cuts, burns, scalds, sunburns, acne, diabetic ulcers and bedsores caused by prolonged periods of bed. Wound healing is a complex and slow process, and new epithelial tissues and connective tissues are formed by migration and proliferation of cells in wound treatment, so that the effects of promoting cell migration, differentiation and proliferation and the like contribute to wound healing. Previous studies (Paul Martin, "work health-Aiming for Perfect Skin Regeneration", p75-81, SCIENCE, vol.276,4april, 1997) have shown that so-called "EGF family" including epidermal growth factor (epidermal growth factor, EGF), transforming growth factor-alpha (transforming growth factor-alpha, TGF-alpha) and heparin-binding epidermal growth factor (HB-EGF) are released in large amounts at the site of epidermal lesions, and are critical for regulating keratinocyte proliferation at the Wound edges. In addition, studies have also found that exogenous epidermal growth factor and transforming growth factor-alpha, when applied to burn sites on the backs of pigs, enhance their regeneration of epidermal cells (G.L.Brown et al, J.Exp.Med.163,1319 (1986); G.S. Schultz et al, science 235,350 (1987)). These growth factors act on the epidermis and act as cellular mobgens (motogens) and mitogens (mitogens) to drive wound closure (Y.Barrandon and H.Green, cell 50,1131 (1987)).
Previous in vitro model studies on the recovery of intestinal epithelial cells (intestinal epithelial cell) with various cytokines (cytokines) and peptide growth factors (peptide growth factors) showed that: transforming four factors, growth factor-alpha, epidermal growth factor, interleukin-1 beta (IL-1 beta) and interferon-gamma (IFN-gamma), promotes the production of biologically active (biological activity) TGF-beta 1peptide on injured IEC-6 intestinal monolayer cell membranes and enhances the recovery of intestinal epithelial cell wounds by 2.3-to 5.5-fold (Diagnass, A.U., podolsky, D.K., gastroenterology,105 (5), 1323-1332 (1993)).
In the prior art, some agents for promoting wound healing are based on growth factors, but using such exogenous growth factors for wound treatment have the following disadvantages: firstly, the growth factors are unstable proteins, are easy to decompose when stored, and can be digested and destroyed before entering blood when orally taken; secondly, the growth factors are absorbed by the human body slowly and can be rapidly decomposed, so that the externally applied growth factor ointment has limited effect; (III) many growth factors are species specific, such as by parenteral administration, and are recognized as foreign species and are rejected, eliciting a dangerous immune response. For the above reasons, exogenous growth factors are not ideal wound healing agents. The literature also states that: there is no evidence that exogenous growth factors administered parenterally will reach the skin, connective tissue and supporting tissues. Thus, endogenous growth factors are truly effective in promoting wound healing. The preparation of drugs that produce endogenous growth factors is a primary object of the present invention.
The test of Wound healing effect of rats was carried out by Matsumoto et al in an isotonic solution (isotonic solution) containing 1.8% Ge-132 (H. Matsumoto at., "Restorative effect of organic germanium compound (Ge-132) on dermal in jury", work Medicine 15,6-10 (2016)), which showed that the effect of promoting Wound shrinkage did not significantly differ from that of physiological saline, and the test results were shown in comparative example one as shown in FIG. 1, which showed an effect of promoting Wound shrinkage but did not significantly differ from that of the control group using physiological saline, and were not significantly different from that of the drug of the present invention. It is also an object of the present invention to develop a wound healing drug which has a high effect of promoting wound healing and can inhibit the generation of exudates.
Another component for preparing the medicament of the invention is glucosamine compounds containing active amine groups, including monosaccharides, disaccharides, polysaccharides with different polymerization degrees (such as chitosan oligosaccharide and chitosan) and derivatives thereof, and the like. Glucosamine is a compound in which one hydroxyl group in glucose is replaced by an amine group, and is a natural aminomonosaccharide. Since a large amount of N-acetylglucosamine (N-acetylglucosamine) is contained in chitin (chitosan) of arthropod shells such as shrimp and crab, chitosan or chitosan (chitosan-NH) is obtained by deacetylation of chitin of shells such as shrimp and crab 2 ) The molecular structural formula of the polyglucosamine is shown as formula (I):
formula (I): chemical structural formula of chitosan (chitosan)
General commercial chitosan is not completely deacetylated, and thus, has different contents of N-acetamido groups due to the difference in degree of deacetylation (degree of deacetylation) as shown in formula (I).
Chitosan is a polysaccharide, which can be further depolymerized (depolymerization) and deacetylated with depolymerization by chemical hydrolysis, enzymatic decomposition or high energy impact (high energy impact) to obtain an oligosaccharide with a low polymerization degree (degree of polymerization, DP) and a high deacetylation degree, namely chitosan (COS-NH 2). The chemical structure of chitosan is similar to that of chitosan, except that the polymerization degree is low and the deacetylation degree is high. For the sake of each, the literature defines chitosan as polyglucosamine having a degree of polymerization DP.ltoreq.20 and an average molecular weight of.ltoreq.3900 daltons (Da) (V.K.Mourya, N.N.Inamdar, and Y.M. Choudhari, "Chitooligosacharides: synthesis, characterization and Applications", polymer Science, ser.A,2011,Vol.53,No.7,pp.583-612.).
Glucosamine monosaccharides can also be obtained from further depolymerization of chitosan or chitosan oligosaccharides, which is also the main route currently in use for the preparation of glucosamine monosaccharides. Among them, the enzymatic depolymerization method is favored because of its mild reaction conditions, high yield and specificity, and the fact that the structure of glucosamine is not changed (Pan et al, "Preparation of glucosamine by hydrolysis of chitosan with commercial. Alpha. -amylase and glucoamylase", J.Zhejiang Univ-Sci B (Biomed & Biotechnol) 2011,12 (1): 931-934). The molecular weight of glucosamine monosaccharide is 179.17, the polymerization degree is 1, and the glucosamine monosaccharide has similar characteristics to chitosan in the preparation and application of the medicament.
Chitosan is a bioabsorbable polymer and has been widely used in various industries such as food, materials, medical treatment, agriculture, environmental protection, etc. Chitosan has excellent biocompatibility and no toxicity, and thus is used as a gene transfer vector for gene therapy (gene therapy), and also has been used for controlled release of drugs (controlled release) to treat various diseases including cancer because of its superior adhesion properties to facilitate the transport of various drugs on cell membranes; in addition, it has the physiological functions of inhibiting bacteria, coagulating blood, accelerating cell proliferation, promoting skin tissue repair, preventing tissue adhesion, inhibiting scar formation, protecting articular cartilage, etc. and is used in stopping bleeding and wound healing.
Chitosan is insoluble in water, but in its application, whether prepared as a hydrosol, hydrogel, solid particles, film or fiber, etc., must be achieved by dissolution. Therefore, the preparation method of chitosan solution, which has simple development procedure, short reaction time, no need of additional solvent and no pollution of toxic components, has been a problem in medical application. It is also an object of the present invention to solve this problem.
Unlike chitosan, chitosan has a higher degree of deacetylation, a lower degree of polymerization, a lower molecular weight and viscosity, and has high water solubility, and also has more remarkable pharmacological properties such as antibacterial property, antioxidant property, anti-inflammatory property, antihypertensive property, and drug/DNA delivery function. In addition, chitosan also exhibits anti-diabetic, anti-obesity, anti-HIV-1, anti-alzheimer's disease, cholesterol-lowering, calcium absorption enhancing, and hemostatic effects, and has a higher cell transduction (cellular transduction) than chitosan and a property of being completely absorbed through intestinal epithelium, etc. Therefore, it has been demonstrated to be suitable for tissue engineering, drug or gene delivery, multi-drug resistance against chemotherapy, etc., and its medical use is no more than chitosan, or even more than chitosan. Up to now, there is no discovery that chitosan Ding Ju and chitosan induce secretion of interferon, a derivative growth factor, but studies have shown that chitosan can induce release of platelet-derived growth factor-AB (PDGF-AB) and transforming growth factor- β1 (TGF- β1) from platelets (He Liu et al, "A functional chitosan-based hydrogel as a wound dressing and drug delivery systemin the treatment of wound healing", RSC adv, 2018,8,7533). The above results of studies on glucosamine compounds and organogermanium compounds clearly show that the pharmacological properties of glucosamine compounds and organogermanium compounds have complementary actions and can exert the synergistic effect of medical efficacy (synergistic effect), so that the medicament of the invention has excellent efficacy.
Disclosure of Invention
The invention provides a medicine prepared from an organogermanium compound and a glucosamine compound and application thereof. The invention also has the following objects, including: firstly, preparing a liquid-type organic germanium medicament, so that the organic germanium medicament is convenient to use and is prevented from being polluted by solid germanium dioxide; secondly, the preparation method of chitosan solution has simple development procedure, short reaction time and no pollution of toxic components; (III) preparing a medicament with the biochemical characteristics and the medical effects of the organic germanium compound and the glucosamine compound; and fourthly, preparing a medicament which can generate endogenous transforming growth factors in human bodies and animals, promote the rapid healing of wounds and inhibit exudates generated by the wounds.
In order to achieve one or a part or all of the above objects or other objects, the present invention provides a method for preparing a glucose amine compound by reacting an organogermanium compound having a carboxylic acid group (-COOH) with a glucose amine compound, and reacting the glucose amine compound with a reactive amine group (-NH) by utilizing the hydrogen ion of the carboxylic acid group of the organogermanium compound 2 ) The protonisation of the above-mentioned components can be used for preparing water-soluble salt medicine, said salt medicine possesses high water solubility, can be dissociated in tissue fluid, and can produce biochemical property, pharmacological property and medical effect of its components. These biochemical, pharmacological and medical effects include: analgesic, anti-inflammatory, antioxidant, antihypoxic, immunomodulating, antiviral and interferon secretion inducing, transforming growth factor derived etc. effects derived from the organogermanium compound component, and antibacterial, antioxidant, anti-inflammatory, antihypertensive, drug/DNA transfer, antidiabetic, antiobesity, anti-HIV-1, anti-alzheimer's disease, cholesterol lowering, calcium absorption enhancing, haemostatic, cell transduction effects, and properties which are wholly absorbable through intestinal epithelium. The complementarity of the above effects provides the medicament of the present invention with excellent therapeutic efficacy in a variety of ways including, but not limited to, promoting wounds (including wounds, lacerations, abrasion injuries, incised wounds, burns, scalds Wound, sunburn, acne, diabetic ulcer, bedsores caused by long-term bedridden, etc.). The excellent medical effect will be demonstrated hereinafter by taking Ge-132, chitosan and chitosan as examples of the preparation of the drug of the present invention and the application of the drug in promoting wound healing.
The foregoing description is only an overview of the present invention, and is intended to be implemented in accordance with the teachings of the present invention, as well as the preferred embodiments thereof, together with the following detailed description of the invention, given by way of illustration only, together with the accompanying drawings.
Drawings
FIG. 1 shows the change with time of the wound size ratio of a rat of comparative example.
Fig. 2 shows the change over time in a rabbit wound size ratio of example one.
Fig. 3 shows the change over time in the wound size ratio of the rabbits of example two.
Fig. 4 shows the change over time in the wound size ratio for the three rabbits of the example.
Detailed Description
Organogermanium compounds bearing carboxylic acid groups suitable for the preparation of the medicaments of the present invention include, but are not limited to, organogermanium sesquioxides (organogermanium sesquioxide), germanes (germanes), heterogermanium tricyclic compounds (germatrans), helical germanium compounds (spirogermanium compounds), germanium porphyrin compounds (germanium porphyrines), and dicyclopentadienyl germanium compounds (germanocenes), the most typical of which are bis-carboxyalkyl germanium sesquioxides (bis-carboxyalkyl germanium sesquioxide), the monomers of which have the formula (II):
Wherein R1, R2, R3 may be H, substituted or unsubstituted lower alkyl (alkyl) such as methyl (methyl) or ethyl (methyl), aryl (aryl), heteroaryl (heteroaryl), substituted or unsubstituted amino (amino group) or amido(amido group) and the like; x may be H, K, na, basic amine (basic amino group), aryl (aryl) or heteroaryl (hetaryl) and the like. When R1, R2, R3 and X in formula (II) are H, the bis-carboxyethylgermanium sesquioxide (bis (carboxyethyl) germanium sesquioxide) is a solid polymer of formula n (GeO) 1.5 CH 2 CH 2 COOH) 2 Abbreviated as Ge-132. When X in the formula (II) is K, na, basic amino (basic amino group), aryl (aryl) or heteroaryl (heteroaryl) or the like, the white Ge-132 powder can be obtained by acidification and crystallization with concentrated hydrochloric acid. In addition, the chemical formula of the hetero nitrogen germanium tricyclic compound (germatrans) is shown in formula (IV):
wherein R is cinnamic acid group [ -CH (C) 6 H 4 OH)CH 2 COOH]Caffeic acid radical [ -CH (C) 6 H 3 (OH) 2 )CH 2 COOH]Or one of its derivatives. The helical germanium compound is at least one selected from the group consisting of: 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0)]Undec-1-yl) caffeic acid (3- (2, 8, 9-trioxa-aza-1-germatricyclic- [3,3,3,0)]-undecane-1-yl) cafleic acid), 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0 ]-undecan-1-yl) -10-hydroxy-decanoic acid (3- (2, 8,9-trioxa-aza-1-germatricyclo- [3,3,3,0)]-undecan-1-yl) -10-hydroxy-decanoic acid), 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0]-undecan-1-yl) -10-methoxy-decanoic acid (3- (2, 8,9-trioxa-aza-1-germatricyclo- [3,3,3,0)]-undecan-1-yl) -10-methoxy-decanoic acid, 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0)]-undecan-1-yl) -10-ethoxy-decanoic acid (3- (2, 8,9-trioxa-aza-1-germatricyclo- [3,3,3,0)]-undecan-1-yl) -10-ethoxy-decanoic acid, 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0)]-undecan-1-yl) -10-phenyl-decanoic acid (3- (2, 8,9-trioxa-aza-1-germatricyclo- [3,3,3,0)]-undecane-1-yl)-10-phenyl-decanoic acid)。
Ge-132 is the most representative bis-carboxyalkyl germanium sesquioxide, and has the structural formula shown in formula (III):
ge-132 is soluble in water. The reaction dissolved in water is shown as formula (1):
n(GeO 1.5 CH 2 CH 2 COOH) 2 +3nH 2 O=2nGe(OH) 3 CH 2 CH 2 COOH (1)
ge-132 is dissolved in water to form carboxylic acid named 3- (trihydroxygermyl) propionic acid (THGP), and its chemical formula is Ge (HO) 3CH2CH2COOH.
Description of the principles of drug preparation
Chitosan is one of the glucosamine compounds used in the present invention, and will be described by way of example. As shown in formula (I), chitosan has 3 common reactive functional groups in its chemical structure, namely amine group (amino group), primary hydroxyl group (primary hydroxyl group) and secondary hydroxyl group (secondary hydroxyl group), so it has higher reactivity than general chitosan, but is insoluble in water. In various medical applications of chitosan, it is mainly made into sol, gel, film or fiber forms, and liquefaction is the first problem faced in making these forms of medicament. Previous studies have revealed that chitosan can only be dissolved in Acid solutions, which is caused by its reactive amine groups being protonated by hydrogen ions (protonation), the solubility being affected by its deacetylation degree, the distribution of acetyl groups on the molecular chain, and the pH of the Acid solution, the Acid structure and other ions contained, etc., and thus studies have resulted in a variation of the highest pH value that can be dissolved from pH 6 to pH 6.5 (Domard a. "pH and c.d.measurents on a Fully Deacetylated Chitosan: application to CuII-polymer Interactions" Int.J.Biol.Macromol.,9,98,1987;J.W.Park and H.K.Choi, "Acid-Base Equilibria and Related Properties of Chitosan" bull.korean chem. Soc., vol.4, no.8,1983; rinaudo, m.; pavlov, g.; desbrires, j. "Solubilization of Chitosan in Strong Acid Medium" int.j. Anal. Ray.5, 267-276,1999), wherein further studies by Rinaudo et al indicate that chitosan is in a state of being protonated by more than 50% of the amine groups.
The carboxylic acid THGP formed by dissolution of Ge-132 in water is a weak acid, and the solubility of Ge-132 in water at 25℃is 1.28 g/100 milliliters (ml) according to the test of Sara M.Ogwapit et al (Sara M.Ogwapit et al, "Analysis of Ge-132and development of a simple oral anticancer formulation", bioscience Horizons, vol.4, no.2, june 2011), at which the pH of the solution is 3.06-3.12. The experiment of the invention shows that the THGP solution and the acetic acid solution are the same, and have good dissolution effect on chitosan, wherein the dissolution effect is due to the hydrogen ion of the carboxylic acid group of the THGP, and the dissolution effect is due to the reactive amino (-NH) of chitosan 2 ) The protonation is performed and the reaction is shown as a formula (2).
The product of the reaction of formula (2) is chitosan N-3- (trihydroxygermyl) propionate (chitosan-N-3-trihydroxygermyl propionate, chitosan-N-THGP), a water-soluble salt compound in the form of a polycationic polymer (polycationic polymer) which dissociates in water to a 3- (trihydroxygermyl) propionate anion (Ge (OH) 3 CH 2 CH 2 COO-) and protonated chitosan cation (chitosan-NH) 3 + ) Thus, the biochemical characteristics of the plasma are exhibited.
Experiments in accordance with the present invention show that the reaction of formula (2) is a gentle process. When chitosan is added to a 3- (trihydroxygermyl) propionic acid solution, chitosan is protonated to produce a pale orange, viscous reaction product solution containing chitosan-N-THGP, which is a colloidal solution. With the increase of the chitosan addition amount, the pH and the viscosity of the reaction product liquid are increased. According to the experiment of the invention, when chitosan with the deacetylation degree of 91.35% and the molecular weight of 100-130kDa is used for preparing the medicine, when the dissolved chitosan reaches 5% of the total weight of the generated solution, the viscosity (25 ℃) can rise to about 15,000cp, and when the chitosan is added to a certain degree, the carboxylic acid group hydrogen ions of THGP are exhausted, and when the reaction of the formula (2) is finished, the chitosan is not dissolved any more, the generated solution is clear and transparent and shows turbidity, and the pH value of the generated solution is about 6.
The variability of chitosan polymerization degree, deacetylation degree, molecular weight and the like can influence the solubility of chitosan, so that the quality of the medicine is difficult to control. Therefore, the invention adopts acids with good dissolving capacity to chitosan, including but not limited to acetic acid, formic acid, hydrochloric acid or sulfuric acid, etc., as pH regulator, so that the chitosan can be dissolved without completely relying on 3- (trihydroxy germanyl) propionic acid, thus, not only can each functional raw material be dissolved in a preset required proportion, but also the stable appearance and characteristics of the medicine can be ensured. Besides the ideal pH regulator, the acidic agent can also replace the effect of 3- (trihydroxy germanyl) propionic acid, so that the dosage of chitosan and 3- (trihydroxy germanyl) propionic acid can be freely regulated during the preparation of the medicine, and is not limited by the reaction equivalent. Therefore, the pH regulator not only can help to prepare a medicine solution with stable, transparent and clear pH, but also can play the role of a viscosity regulator at the same time, and the medicine can obtain the required viscosity without adding a thickening agent, so that the purity of medicine components can be ensured, and the pollution is reduced; similarly, the addition of basic pH modifiers, including but not limited to ammonium hydroxide or alkali and alkaline earth hydroxides, such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, and the like, may promote the dissolution of the organogermanium compound with carboxylic acid such that its content in the medical fluid is no longer limited by the equivalent of reaction with chitosan. Thus, the medicine of the invention can further contain high water-soluble salts formed by the alkaline agent and the organic germanium compound, which is beneficial to improving the 3- (trihydroxy germanyl) propionic acid root (Ge (OH) of the medicine 3 CH 2 CH 2 COO-) concentration and corresponding medical efficacy are also part of the present invention. According to the study of the invention, the salts formed by the alkaline agents and Ge-132 have good effect of promoting wound healing, wherein the alkaline agents and the salts are separated by calcium ionsThe medicine has hemostatic effect, so that the prepared medicine can also be favorable for hemostasis of wounds when calcium hydroxide is used as an alkaline agent, and experiments prove that the medicine can be used for stopping bleeding of wounds.
The above chitosan-containing produced liquid has similar typical characteristics to other chitosan-containing organic acid solutions, including: (1) The generated liquid is in a sol (sol) state when being acidic, and is converted into a gel (gel) state when being neutral or alkaline; (2) The salt compound (chiro-N-THGP) produced by the reaction is insoluble in organic solvents including alcohols. Therefore, the sol may be used in the form of an ointment, a liquid, or the like, or in the form of other forms by utilizing these characteristics. For example: the sol is prepared into neutral or alkaline, and the gel is gelled (gel) to be made into hydrogel; dispersing in 95% alcohol or organic solvent to obtain precipitate, filtering, and vacuum drying at low temperature to obtain powder; the sol may also be electrospun alone or in combination with other suitable polymeric compounds such as, but not limited to, polyvinyl alcohol (Polyvinyl alcohol, PVA) using electrospinning techniques (electrospinning technology) to produce fibers, fibrous membranes (El-Refaie Kenawy et al, journal of Controlled Release 81 (2002) 57-64; zheng-Ming Huang et al, composites Science and Technology 63 (2003) 2223-2253; Y.Liu et al, J.biomed.Mater.Res.part B: appl biomatter.90B: 492-502, 2009) or nonwoven fabrics, etc. In addition, experiments of the invention also show that the sol liquid has good mixing property with glycerol, and the sol liquid is uniformly mixed with a proper amount of glycerol (boiling point of 290 ℃), then the mixture is coated into a thin layer, and then the thin layer is heated to properly remove water, so that a soft and transparent film can be prepared. Therefore, the medicine of the present invention may be prepared into powder, film, fiber film, non-woven fabric, etc. in addition to liquid, paste, emulsion. The medicament of the invention may also optionally be supplemented with at least one auxiliary agent and is suitable for in vivo or in vitro administration.
In addition to chitosan, the present invention also uses chitosan and 3- (trihydroxygermyl) propionic acid for pharmaceutical preparation. The experimental result of the invention for preparing chitosan with the average molecular weight of 1270Da by ferment degradation shows that the chitosan aqueous solution is weak acid, and the pH of the 1% solution at 25 ℃ is 5.4. The concentration has little effect on the pH, and when the concentration is increased from 1% to 10%, the pH does not change obviously; but temperature changes have a significant effect on pH. The temperature increases and the pH decreases. Taking 10% chitosan solution as an example, when the temperature is raised from 20 ℃ to 55 ℃, the pH is reduced from 5.65 to 4.49, and the change trend is nearly linear.
The protonation reaction of chitosan with 3- (trihydroxygermyl) propionic acid, which can be represented by formula (2), the reaction product is N-3- (trihydroxygermyl) propionic acid chitosan (COS-N-3-trihydroxygermyl propionate, COS-N-THGP), which is also a salt compound that dissociates into 3- (trihydroxygermyl) propionate anions ((HO) in water 3 GeCH 2 CH 2 COO-) and protonated chitosan (COS-NH) 3 + ) Cations and thus possess the biochemical properties of both.
When the chitosan is used for preparing the medicine, the operation mode is the same as that when the chitosan is used for preparing the medicine. When chitosan is added into 3- (trihydroxy germanyl) propionic acid solution, the solution is dissolved to form a coffee-colored reaction product solution. Since chitosan has high water solubility, the dissolution is not completely controlled by the protonation reaction of amine groups, and the pH of the reaction product is much lower than that prepared with chitosan. Because the protonation reaction with chitosan consumes more Ge-132 and promotes the dissolution of Ge-132, the concentration of 3- (trihydroxy germanyl) propionic acid radical in the reaction generating solution can be higher than the saturation concentration in the Ge-132 aqueous solution as the dissolution of chitosan is the same. Since the polymerization degree and molecular weight of chitosan are low, the viscosity of the reaction product liquid is low, the problem of operation influence caused by high viscosity is avoided, and the need of lowering the pH value to help the dissolution of chitosan is avoided, otherwise, alkali liquor including but not limited to ammonia water or hydroxides of alkali metals and alkaline earth metals such as sodium hydroxide, calcium hydroxide and the like can be optionally added to moderately raise the pH value or help the dissolution of Ge-132 if necessary, so as to improve the concentration of 3- (trihydroxy-germanyl) propionate in the medicament as described above; when calcium hydroxide is used as the pH regulator, calcium ions have a hemostatic effect, so that the hemostatic effect of the wound is facilitated. The medicine of the present invention may be also prepared into liquid, paste, powder, film, etc. with proper excipient and additive and through adding chitosan gel liquid, and the powder may be prepared into powder with high hygroscopicity and no adhesion.
According to the above description, the preparation steps of the medicine of the invention are summarized as follows: material preparation: according to the amount and composition of the medicine to be prepared, the required raw materials including organic germanium compounds such as Ge-132, glucosamine compounds such as chitosan or chitosan oligosaccharide, pH regulator, deionized water, etc. are prepared; presetting water, stirring and heating: placing the deionized water with the required amount into a heatable stirring reaction tank, stirring, and heating or not heating according to the situation; (III) adding an organogermanium compound: feeding a desired organogermanium compound in dry weight to a reaction tank, dispersing and dissolving in water under stirring to produce 3- (trihydroxygermyl) propionic acid; (IV) adding a glucosamine compound: when the water temperature reaches a preset temperature, the glucosamine compound is input into the reaction tank, and the poor dispersion of solid powder particles caused by too fast input is avoided; and (V) continuously stirring to complete the protonation reaction: stopping heating (if heating) at proper time after the glucosamine compound is completely input, and continuously observing that the pH of the reaction generating solution is stable so as to confirm that the protonation reaction is completed; and (six) pH adjustment: adjusting the reaction product liquid to a predetermined pH value by a pH adjusting agent; (seventh) adjusting the weight: deionized water is added to adjust the weight to a preset weight, and the preparation is completed.
The above steps are simple and easy to implement, wherein the matters related to the operation efficiency and the medicine quality control are as follows: in the first step, since chitosan and chitosan are easy to absorb moisture, the moisture resistance during storage is required to be paid attention, and the water content of the chitosan and chitosan is required to be determined during material preparation; the reaction equivalent will vary from one molecular structure to another, and therefore, a batch-wise analytical determination is required. In the second step, the amount of water placed in the reaction tank is kept in mind to allow the subsequent addition of the pH adjustor solution (although the amount is not large); heating or non-heating can be adopted, the heating can promote the dissolution of Ge-132 and accelerate the reaction, but the subsequent cooling is time-consuming; at room temperature, for example, below 25℃it is preferable to heat, but it is preferable to not exceed 50 ℃. In step (three), the organogermanium compound feed may be added in one portion, or in divided portions; the addition may be performed before the water is heated, or after the heating is completed. In the fourth step, according to the predetermined preparation composition of the medicine, chitosan or chitosan is fed in batch mode, wherein, when the medicine is prepared from chitosan, the viscosity of the reaction product liquid can rise along with the addition of chitosan, and the flow pattern (flow pattern) of the product liquid during stirring can also be changed, so that the bad dispersion of particles caused by too fast feeding is avoided, and a stirrer suitable for high-viscosity fluid is also adopted; when chitosan is used for preparing medicines, the viscosity of the generated liquid is low due to high water solubility, so that the problem that the viscosity influences the operation is avoided. In step (five), a stable pH is measured to indicate that the protonation reaction is completed, and a subsequent step can be performed; since the pH of the resulting solution is affected by temperature, temperature correction is required for measurement. In the step (six), temperature correction is required during the adjustment of pH, and attention should be paid to the possible damage to the pH electrode caused by the viscosity of the liquid medicine, thereby preventing the influence on the measurement accuracy. In the seventh step, the adjustment of the components is preferably performed on a weight basis so as to avoid the influence of temperature change without waiting for cooling.
The above medicines are disclosed in the present invention, and in order to make the features, objects and advantages of the present invention more obvious, the following specific examples of the use of the medicines in promoting wound healing are given by way of illustration, and should not be taken as limitations of the kinds of medicines of the present invention and other medical uses of the medicines of the present invention.
Comparative example one of wound healing effect: the literature discloses that Hiroko Matsumoto et al used Ge-132 solution, i.e., 3- (trihydroxygermyl) propionic acid solution, for studies of healing of rat (rats) skin wounds (Hiroko Matsumoto et al, "Restorative effect of organic germanium compound (Ge-132) on dermal in jury", wound Medicine, vol.15, dec.2016, P6-10) in an isotonic solution containing 1.8wt% Ge-132Treatment of the wounds was performed and compared with normal saline as a control group. The study found that on days 1, 3, 7, and 14, the applied wound sizes were 1.45.+ -. 0.23 square centimeters (cm) 2 )、1.45±0.13cm 2 、0.780±0.124cm 2 And 0.050+ -0.013 cm 2 . The wound sizes of the control group to which physiological saline (physiological saline solution, P.S.) was administered were 1.77.+ -. 0.36cm, respectively 2 、1.73±0.13cm 2 、0.942±0.150cm 2 And 0.108.+ -. 0.049cm 2 . For clarity of comparison, the comparison of the wound size ratios at days 1, 3, 7 and 14 was performed based on the above results with the median of the wound area of the first day being 100%, and the results are shown in fig. 1, in which two curves representing the change in the wound size ratio between the administration group and the control group during the administration are very close, showing that the effect of promoting wound healing by the Ge-132 isotonic solution is not particularly remarkable.
Embodiment one: example one is the use of the present medicament for wound healing treatment to demonstrate the advancement of the present invention, the use of the present medicament comprising: (1) 3wt% Ge-132 equivalent and 4.5% chitosan equivalent (code: 3% Ge-CTS), (2) 3% Ge-132 equivalent and 4.5% chitosan equivalent (code: 3% Ge-COS), (3) 1.5% Ge-132 equivalent and 2.25% chitosan equivalent (code: 1.5% Ge-CTS), which were obtained by diluting 3% Ge-CTS with deionized water. For comparison with comparative example one, the organogermanium component of the above experimental drug was measured in terms of the equivalent of Ge-132 contained, and the expression "3% Ge-132 equivalent" means that the weight of Ge-132 used in the preparation of the drug was 3% of the weight of the drug produced. Calculated from the relationship of the Ge-132 molecular weight 339.4222,3- (trihydroxygermyl) propionic acid molecular weight 199.75, and the reaction equivalent of formula (1), the Ge-132 content of 3% is equal to the 3- (trihydroxygermyl) propionic acid content of 3.531%, or the germanium element (atomic weight 72.64) content of 1.284%.
These examples are intended to demonstrate the effect of the present invention on wound healing and should not be taken as limiting the scope of the claims. In addition, in order to understand and compare the wound healing effect of different Ge-132 salts, the present invention also performed a wound healing experiment with a 3- (trihydroxy germyl) calcium propionate solution (code: 3% Ge-Ca) containing 3% Ge-132 equivalent, and examined the wound healing effect of Ge-132 alkaline earth metal salts as example two.
Example preparation of experimental drugs:
the preparation is carried out according to the method and the steps.
Preparing materials:
the organic germanium compound is Ge-132, namely, fine Ge-132 powder with the purity of more than 99.95% of commercial vendors is taken, is firstly dissolved in deionized water at 95 ℃ to form saturated aqueous solution, is filtered by Whatman No. 3 qualitative filter paper, is collected in a beaker, is stirred and cooled to room temperature to crystallize Ge-132, is subjected to vacuum filtration, is washed by deionized water, is dried until the water content is 0.15%, and is smashed into powder for standby. The glucosamine compound is chitosan and chitosan, which are both commercial products (Chengli Co., ltd.), wherein the deacetylation degree of chitosan is 91.35%, the molecular weight is 100-130kDa, and the water content is 9.47wt%; the deacetylation degree of chitosan is 91.35%, the average molecular weight is 1270Da, and the water content is 8.32wt%. The pH adjuster used was a 10wt% aqueous glacial acetic acid solution. Since chitosan is hygroscopic, it is used by drying and removing water, and weighing dry weight.
Preparation of experimental drug 3% Ge-CTS:
the preparation method comprises the following steps: (1) 180 grams of deionized water is placed in a 500ml beaker, 6 grams of Ge-132 powder with dry weight is added, and electric stirring is started and the mixture is heated to 50 ℃; (2) Taking 9 g of chitosan (namely 1.5 times of the weight of Ge-132) on dry weight, and slowly adding the chitosan into the stirred Ge-132 solution; (3) After the chitosan is fed, stirring is continued and the temperature is maintained for 30 minutes, heating is stopped, the temperature is reduced to 25 ℃, and the pH value of the generated liquid is measured to be 6.03; (4) adjusting the pH of the resultant liquid with a pH adjuster=5.81; (5) Deionized water is added to adjust the weight to 200 g, and the mixture is uniformly mixed to obtain light orange yellow viscous liquid. The chitosan 9 g (1.5 times the weight of Ge-132) used in the above preparation was experimentally determined in advance to be the weight required for the protonation reaction with 6 g of Ge-132.
Preparation of experimental drug 3% Ge-COS:
the preparation was performed using the same procedure and temperature as for the preparation of 3% Ge-CTS, using the same Ge-132 but without the use of a pH adjuster. The prepared chitosan 3- (trihydroxy germyl) propionate is a coffee solution with low viscosity, the content of Ge-132 is 3wt%, the content of chitosan is 4.5wt%, and the pH of the chitosan at 25 ℃ is 3.02. The above is advantageous in comparison with chitosan, so that the weight of chitosan used is also 1.5 times that of Ge-132.
Preparation of experimental drug 3% ge-Ca:
(1) 180 g of water was placed in a 500ml beaker and stirred with an electromagnetic heating stirrer, and 6.01 g of Ge-132 powder (dry weight 6 g) was added to the water. (2) Another Merck GR-grade Ca (OH) 2 1.31 g of the powder was added to a beaker and heated to 45℃to bring the Ge-132 powder together with Ca (OH) 2 After the powder was dissolved and the total weight of the solution was adjusted to 200 g by adding water after 30 minutes, it was filtered through Whatman No. 3 qualitative filter paper to obtain 3% Ge-Ca, which was 3% Ge-132 equivalent, and the pH at 25℃was found to be 7.04.
Animal test of wound healing:
the animals tested were New Zealand Minimal Disease (MD) grade rabbits weighing between 2.3 and 2.5 kg at birth for 100 days. Two days before the experiment, the rabbits are firstly put on the back jacket for preventing licking so as to be used to, the jacket can prevent the licking of the rabbits from touching the wound, but the excretion of the rabbits is not hindered, and the administration and observation photographing can be easily carried out. The experiment is started on the same day, the hair is removed from the middle area of the back of a rabbit, then 1 or 2 positions are selected on two sides of the spine of the hair removal area as required, the positions of wounds (measured by actual size) of 1.5 cm x 1.5 cm are marked, the distance between the edges of the wounds is 4cm, then the predetermined wound is injected with xylestisin-A for anesthesia, then the wound is opened by a biopsy punch and a surgical knife, the skin and the meat on the upper layer of fascia are removed, after the wound is pressed for hemostasis by medical gauze, the wound is cleaned by physiological saline, and finally the medical cotton ball is used for wiping dry, and then the medicine is applied.
The applied dose of the wound is 0.3ml per wound in the first 7 days, and the wound is reduced by the wound after 7 days, so the dose is halved. After wound application, the wound is covered and secured with a 3M breathable polyurethane Film (Tegadarm Film, st. Paul, minnesota). Once every 24 hours, the wound size was smaller than measured after photography using the area measurement function of the PHOTOSHOP software. The control group wounds were identical to the applied wounds except that they were not applied.
Embodiment one and embodiment two:
in the first example, two drugs of 3% Ge-CTS and 3% Ge-COS were used, and in the second example, 3% Ge-Ca was used. The three drugs all contained 3% Ge-132 equivalent concentration, each drug created 2 wounds on both sides of the spine in the above manner with three rabbits, for three drug and no drug administration control groups, and the wound sizes were measured on days 1, 3, 7, and 14. Table one shows the experimental results of the 3% Ge-132 and 3% Ge-COS of example one, the 3% Ge-Ca of example two, and the control group, the data contained wound area size, and for comparison, the wound size ratio was changed based on the wound size on day 1 (i.e., 100%).
Table one: experimental results of examples one and two
Generally, surgical wounds, whether administered or not, may be approximated by healing for about two weeks. When the drug has the effect of promoting healing, the shrinkage rate of the wound to be applied is obviously faster than that of the wound of the control group without application in the initial stage of the experiment. FIG. 2 shows the results of three rabbits per drug on days 1, 3, 7, and 14 of the example, wherein two curves respectively represent the ratio of the average size of the wound in the drug administration group to that of the wound in the control group, and the distance between the two curves represents the difference of the reduction degree of the wound.
Figure 2 shows that the applied wound, whether 3% Ge-CTS or 3% Ge-COS, was rapidly contracted at the early stage of application and maintained a significantly faster healing rate throughout the wound than the control group. The wound reduction rates were very close to, and no significant difference was observed between the application of 3% Ge-CTS and the application of 3% Ge-COS. The wound of the control group had a marked expansion on the third day, which could be attributed to the occurrence of inflammation, whereas the wound applied with the drug did not. The experimental results of example one fully demonstrate that Ge-CTS and Ge-COS have very significant promoting effects on wound healing, which should be attributable to the production of transforming growth factors, and that drugs inhibit the occurrence of inflammation.
Embodiment two: wound healing experiments with Ge-132 alkaline earth salts
The change in the ratio of average wound sizes for example two, performed at 3% Ge-Ca, is shown in figure 3. Wounds to which 3% Ge-Ca was applied had the phenomenon of enlargement on the third day, but the applied group had significantly less enlargement than the non-applied control group. The wound reduction rate of the applied group was superior to that of the control group and also superior to that of the 1.8% Ge-132 isotonic solution of the comparative example shown in FIG. 1, but not as effective as the application of 3% Ge-CTH with 3% Ge-COS as in example one.
Embodiment III: healing efficacy experiment of Low concentration Ge-CTS
To understand the effect of the concentration of the drug of the present invention on wound healing effect, three rabbit wounds numbered D, E and F were tested for healing with 1.5% Ge-CTS. In the same manner as in example, a wound of about 1.5cm x 1.5cm (based on the actual size) was made on each side of the spine of each rabbit, 1.5% ge-CTS was applied to one wound, the dose was also applied as in example one, and the other wound was not applied as a control, and the test results are shown in table two.
And (II) table: experimental results of example three
FIG. 4 is a graph showing the change in the average area ratio of wounds on days 1, 3, 7, and 14 (100% on day 1) of Table II, showing that the wound to which 1.5% Ge-CTS was applied was significantly reduced in the first 7 days compared to the control group to which no drug was applied, and the effect was comparable to or significantly better than that of comparative example one to which 3% Ge-CTS was applied, showing that Ge-CTS also had a significant effect of promoting wound healing at a halved concentration, and was significantly better than comparative example one to which 1.8% Ge-132 isotonic solution was applied.
While the invention has been described with respect to preferred embodiments, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention, and that any such changes and modifications as described in the above embodiments are intended to be within the scope of the invention.
Claims (29)
1. A medicament comprising a water soluble salt compound prepared from an organogermanium compound having a carboxylic acid group and a glucosamine compound having a reactive amine group, the protonation of the reactive amine group of the glucosamine compound being via a hydrogen ion of the carboxylic acid group of the organogermanium compound; wherein the glucosamine compound is selected from at least one of the following: glucosamine monosaccharides, chitosan oligosaccharides, chitosan.
2. The pharmaceutical according to claim 1, wherein the pharmaceutical is a pharmaceutical having biological activity and medical use derived from the organic germanium component and the glucosamine component contained therein.
3. A medicament according to claim 2, characterized in that the medical use from the organogermanium component is any of the following: anti-inflammatory effects, antiviral effects, secretion-inducing interferon effects, derivative transforming growth factor effects, and wound healing effects.
4. A medicament according to claim 2, characterized in that the medical use from the glucosamine component is any one of the following: antibacterial, antiinflammatory, and hemostatic effects.
5. The medicament of claim 1, wherein the organogermanium compound having carboxylic acid groups is at least one selected from the group consisting of: organogermanium sesquioxides, germanes, heteronitrogen germanium tricyclic compounds, helical germanium compounds, germanium porphyrin compounds, and dicyclopentadienyl germanium compounds.
6. The medicament of claim 1, wherein the chitosan has a molecular weight <3,900da, degree of deacetylation >90%, and the chitosan has a molecular weight <130kDa, degree of deacetylation >90%.
7. The medicament of claim 5, wherein the organogermanium sesquioxide has a monomer formula of formula (II):
Wherein R1, R2, R3 may be H, substituted or unsubstituted lower alkyl such as methyl or ethyl, etc., aryl, heteroaryl, substituted or unsubstituted amino or amido, etc.; x may be H, K, na, basic amino, aryl or heteroaryl, etc.
8. The drug of claim 7, wherein the organogermanium sesquioxide is bis-carboxyethyl germanium sesquioxide (Ge-132).
9. The medicament of claim 5, wherein the hetero-nitrogen-germanium tricyclic compound has a chemical formula as shown in formula (IV):
wherein R is cinnamic acid group [ -CH (C) 6 H 4 OH)CH 2 COOH]Caffeic acid radical [ -CH (C) 6 H 3 (OH) 2 )CH 2 COOH]Or any other group containing a carboxylic acid group.
10. The drug of claim 5, wherein the helical germanium compound is at least one selected from the group consisting of: 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0] -undecan-1-yl) caffeic acid, 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0] -undecan-1-yl) -10-hydroxy-decanoic acid, 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0] -undecan-1-yl) -10-methoxy-decanoic acid, 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0] -undecan-1-yl) -10-ethoxy-decanoic acid, 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0] -undecan-1-yl) -10-phenyl-decanoic acid.
11. The medicament of claim 1, wherein the mode of administration is selected from any of the following forms: solutions, emulsions, ointments, hydrogels, powders, films, nonwoven fabrics.
12. The medicament of claim 1, further comprising at least one additive selected from the group consisting of: antibiotics, wetting agents, vitamins, thickeners, excipients, and pH adjusters.
13. The medicament of claim 12, wherein the pH adjuster is at least one of: acetic acid, formic acid, hydrochloric acid, sulfuric acid, ammonia water, sodium hydroxide, calcium hydroxide and magnesium hydroxide.
14. A wound healing medicine is prepared by the following steps:
providing an organogermanium compound having a carboxylic acid group;
providing a glucosamine compound, wherein the glucosamine compound has an active amino group capable of undergoing a protonation reaction and is selected from at least one of the following: glucosamine monosaccharides, chitosan oligosaccharides, chitosan;
mixing the organogermanium compound with the glucosamine compound in water to produce protonation of the carboxylic acid group to the active amine group to form a pharmaceutical solution;
the pH value and weight of the drug solution are adjusted, and excipients are added.
15. The wound healing drug of claim 14, wherein the organogermanium compound bearing a carboxylic acid group is at least one selected from the group consisting of: organogermanium sesquioxides, germane compounds, hetero-nitrogen germanium tricyclic compounds, helical germanium compounds, germanium porphyrin compounds, and dicyclopentadienyl germanium compounds.
16. The wound healing drug of claim 14, wherein the chitosan has a molecular weight <3,900da, degree of deacetylation >90%, and the chitosan has a molecular weight <130kDa, degree of deacetylation >90%.
17. The wound healing drug of claim 15, wherein the organogermanium sesquioxide has a monomer formula of formula (II):
wherein R1, R2, R3 may be H, substituted or unsubstituted lower alkyl such as methyl or ethyl, etc., aryl, heteroaryl, substituted or unsubstituted amino or amido, etc.; x may be H, K, na, basic amino, aryl or heteroaryl, etc.
18. The wound healing drug of claim 17, wherein the organogermanium sesquioxide is bis-carboxyethyl germanium sesquioxide (Ge-132).
19. The wound healing drug of claim 15, wherein the heteronitrogen germanium tricyclic compound has the formula (IV):
Wherein R is cinnamic acid group [ -CH (C) 6 H 4 OH)CH 2 COOH]Caffeic acid radical [ -CH (C) 6 H 3 (OH) 2 )CH 2 COOH]Or any other group containing a carboxylic acid group.
20. The wound healing drug of claim 15, wherein the helical germanium compound is at least one selected from the group consisting of: 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0] -undecan-1-yl) caffeic acid, 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0] -undecan-1-yl) -10-hydroxy-decanoic acid, 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0] -undecan-1-yl) -10-methoxy-decanoic acid, 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0] -undecan-1-yl) -10-ethoxy-decanoic acid, 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0] -undecan-1-yl) -10-phenyl-decanoic acid, 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0] -undecan-1-yl) -hydroxy cinnamic acid.
21. The wound healing drug of claim 14, wherein the step of performing pH adjustment of the drug solution further comprises using a pH adjuster selected from at least one of: acetic acid, formic acid, hydrochloric acid, ammonia water, sodium hydroxide and magnesium hydroxide.
22. The wound healing medication of claim 14, wherein the medication is used to treat any of the following wounds: wounds, lacerations, abrasions, cuts, burns, scalds, sunburns, acne, pressure sores, diabetic ulcers, and the like.
23. The wound healing medication of claim 14, wherein the medication is formulated for use in any of the following forms: solutions, emulsions, ointments, hydrogels, powders, films, nonwoven fabrics.
24. A wound healing drug comprising a salt formed from an organogermanium compound having a carboxylic acid group and at least one compound selected from the group consisting of: glucosamine monosaccharides, chitosan, ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides.
25. The wound healing drug of claim 24, wherein the alkali metal hydroxide is at least one selected from the group consisting of: sodium hydroxide, potassium hydroxide, lithium hydroxide; the alkaline earth metal hydroxide is at least one selected from calcium hydroxide and magnesium hydroxide.
26. The wound healing drug of claim 24, wherein the organogermanium compound bearing a carboxylic acid group is selected from at least one of the following: organogermanium sesquioxides, germane compounds, hetero-nitrogen germanium tricyclic compounds, helical germanium compounds, germanium porphyrin compounds, and dicyclopentadienyl germanium compounds.
27. The wound-healing medication of claim 26, wherein the organogermanium sesquioxide is bis-carboxyethyl germanium sesquioxide (Ge-132).
28. The wound healing drug of claim 26, wherein the heteronitrogen germanium tricyclic compound has the formula (IV):
wherein R is cinnamic acid group [ -CH (C) 6 H 4 OH)CH 2 COOH]Caffeic acid radical [ -CH (C) 6 H 3 (OH) 2 )CH 2 COOH]Or any other group containing a carboxylic acid group.
29. The wound healing drug of claim 26, wherein the helical germanium compound is at least one selected from the group consisting of: 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0] -undecan-1-yl) caffeic acid, 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0] -undecan-1-yl) -10-hydroxy-decanoic acid, 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0] -undecan-1-yl) -10-methoxy-decanoic acid, 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0] -undecan-1-yl) -10-ethoxy-decanoic acid, 3- (2, 8, 9-trioxa-aza-1-germanium tricyclic- [3,3,3,0] -undecan-1-yl) -10-phenyl-decanoic acid.
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