Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • 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
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
  • A61K31/728—Hyaluronic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/16—Emollients or protectives, e.g. against radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/02—Nutrients, e.g. vitamins, minerals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• the present invention relates to an orally administrable hyaluronic acid phospholipid complex, a process for the preparation thereof and a composition comprising the same.
• the complex is characterized in that the phospholipids have a promoting and sustained release effect on the oral absorption of hyaluronic acid, and thus can be widely applied to beauty products and health care products.
• Hyaluronic acid (also known as hyaluronic acid) is an endogenous high molecular mucopolysaccharide mainly found in connective tissues such as skin, cartilage, synovial fluid, cornea and other tissues. The average relative molecular mass is 10 5 ⁇ 10 7 .
• Hyaluronic acid is effective in treating eye diseases and joint diseases with its unique lubricating properties and viscoelastic properties.
• hyaluronic acid has the properties of retaining water, regulating osmotic pressure, promoting wound healing, and scavenging oxygen free radicals in the body. It has been widely used in ophthalmology, orthopedics, dermatology, health foods and cosmetics.
• polysaccharide biomacromolecules such as hyaluronic acid have been widely used in the pharmaceutical field, the amount of oral absorption of such substances in the gastrointestinal tract is small, mainly because of its relatively large molecular mass and poor fat solubility, which is difficult to pass.
• Biofilm barrier a large amount of enzymes in the gastrointestinal tract can degrade polysaccharides and the like.
• Hyaluronic acid is a water-soluble biomacromolecule whose physical properties limit its absorption in the body, especially oral absorption through the gastrointestinal tract.
• the preparation of the transparent shield acid health food on the market is mostly a simple hyaluronic acid solution or a mixture of hyaluronic acid and phospholipid, and the present invention increases the complex of hyaluronic acid and phospholipid.
• the lipophilicity of hyaluronic acid and the high affinity of phospholipids and cell membranes promote the combination of hyaluronic acid molecules and cell membranes to promote absorption, prolong the action time, and improve the oral bioavailability of hyaluronic acid.
• the present invention provides a hyaluronic acid phospholipid complex, a preparation method thereof, and a composition containing the same, and an oral preparation containing the same and other nutrients or active ingredients, in the oral preparation
• Phospholipids have an absorption-promoting and sustained-release effect on hyaluronic acid, and they can also exert synergistic effects, have good effects on human body beauty and health care, and can prevent cardiovascular diseases, respiratory diseases, joint diseases and the like.
• the ratio of the mass ratio of the phospholipid to hyaluronic acid is 0.08 ⁇ 0.5.
• the source of hyaluronic acid in the complex of the present invention is animal tissue extraction, microbial fermentation and genetic engineering preparation, and includes physiologically acceptable salt forms such as sodium salt and calcium salt thereof; and the phospholipid is selected from the following phospholipid species Any of a single phospholipid or a mixture of phospholipids: phosphatidic acid; phosphatidylcholine (lecithin); phosphatidylethanolamine (cephalin); phosphatidylserine; N-methylethanolamine phosphoglyceride N,N-dimethylethanolamine phosphoglyceride; N-acylethanolamine phosphoglyceride; N-2 (hydroxyethyl)alanine phosphatidylglyceride; diphosphatidylglyceride; glycerol phosphate; glucose Aminoglycerol glyceride; 0-amino acid phosphoglyceride; phosphatidylinositol; phosphatidylinosito
• Preferred phosphatidic acid phosphatidylcholine (lecithin), phosphatidylethanolamine (cephalin), phosphatidylserine, glycerol phosphate, phosphatidylinositol, sphingomyelin, dipalmitoylphosphatidylcholine, Palmitoylphosphatidylethanolamine, lysophospholipid; more preferably phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, lysophospholipid; most preferred phosphatidyl Gallbladder Bases, phosphatidylethanolamines, lysophospholipids.
• the invention provides a composition comprising a hyaluronic acid phospholipid complex of the invention, and optionally other active ingredients or nutrients.
• the hyaluronic acid phospholipid complex of the present invention can be formulated into a composition, more particularly various oral preparations, including oral solid preparations such as tablets, capsules, pills, films, granules, powders, etc.; oral liquid preparations , such as oral solutions, suspensions, emulsions, gels, pastes, etc.
• a nutritional additive or other active ingredient may be added on the basis of the basic composition of the oral preparation of the present invention, and the action of the active ingredient may be enhanced by the adhesion of hyaluronic acid, bioadhesion, and the absorption and sustained release of phospholipid.
• the nutritional additives or other active ingredients are: amino acids, nucleic acids, proteins, polysaccharides, celluloses, enzymes, trace elements, macroelements, vitamins, sex hormones, plant hormones, polyunsaturated fatty acids, probiotics , Chinese medicine, etc.
• the mass ratio of the composite of phospholipids and hyaluronic acid is 0. 08 ⁇ 0. 5.
• the present invention provides a method of preparing a hyaluronic acid phospholipid complex of the present invention, the method comprising: providing a hyaluronic acid and a phospholipid having a safety ratio of 1:0.1 to 1:10; The acid or carbodiimide-activated hyaluronic acid is thoroughly mixed with the aqueous phospholipid dispersion in the form of a powder or an aqueous solution, and the complex of the present invention is stirred at a constant temperature.
• the aqueous phospholipid dispersion is obtained by a method for preparing a liposome or by directly hydrating a phospholipid by one or more of mechanical stirring, swirl mixing, and ultrasonication.
• hyaluronic acid and phospholipid The safety ratio is 1:0. 1 ⁇ 1 : 10, the reaction temperature is 28 ⁇ 45 °C, preferably 30 ⁇ 40 °C, and the reaction time is 2 ⁇ 48 h, preferably 4 ⁇ 12 h.
• the aqueous dispersion of the hyaluronic acid solvent and the phospholipid is a physiological saline or a phosphate buffer.
• the preparation process of the hyaluronic acid phospholipid complex of the invention comprises the dissolution of hyaluronic acid and phospholipid, the formation of a phospholipid film, the hydration of a phospholipid membrane, the mixing of hyaluronic acid and a phospholipid dispersion, and the mixing solution is stirred at a constant temperature to obtain the invention.
• the phospholipid dispersion is prepared by rotary evaporation of an organic solution of phospholipid into a film and then adding a dispersion medium by one or more of mechanical stirring, vortex mixing and ultrasonic wave breaking. And hydrated into a uniform dispersion system.
• hyaluronic acid is directly added to the dispersion of phospholipids in the form of an aqueous solution or a powder.
• hyaluronic acid is activated with carbodiimide and then added to the dispersion of phospholipids.
• the phospholipid in the preparation process of the hyaluronic acid phospholipid complex of the present invention, can be firstly formed into a liposome by a conventional method, and then hyaluronic acid is added, and the mixture is stirred at a constant temperature to obtain a complex of the present invention.
• the hyaluronic acid of the invention is a water-soluble polyanionic mucopolysaccharide, which can form a certain hydrophobic region and a hydrophilic region between molecular chains or chains after being dissolved in an aqueous solution.
• the phospholipid is an amphiphilic substance having two long A fatty acid hydrophobic chain and a phosphate based hydrophilic chain.
• Hyaluronic acid and phospholipids can form a complex by a combination of hydrophobic, electrostatic, hydrogen bonding and the like.
• Figure 1 is an infrared spectrum of a mixture of hyaluronic acid, phospholipid, hyaluronic acid and phospholipid, and hyaluronic acid phospholipid complex of the present invention, wherein A: hyaluronic acid; B: egg phosphorus 2
• Figure 2 shows the DSC curves of hyaluronic acid (HA), lecithin (PL), a mixture of hyaluronic acid and phospholipids, and the hyaluronic acid phospholipid complex of the present invention.
• Figure 3 shows the drug concentration time curves of the experimental and control groups in animal experiments.
• hyaluronic acid phospholipid complex 1 mass ratio of hyaluronic acid to phospholipid was 1:3
• Mass ratio of phospholipid to hyaluronic acid involved in complex [ ⁇ L - ( - 3 ⁇ 4)] I 5733 ⁇
• the mass ratio of the phospholipid to hyaluronic acid was 0. 4733.
• complex 1 was identified by attenuated total reflection infrared spectroscopy (MB-HATR) and differential scanning calorimetry (DSC), respectively.
• MB-HATR The sample was tiled on a KBr crystal window, compacted, with a spectral resolution of 8. 0 cm, taking 200 averages, and scanning range 4000 to 500 cm _1 . The results are shown in Figure 1.
• the hydroxyl absorption band in the composite is wider than the mixture, and the wave number of the absorption band shifts to a lower position than the mixture, indicating that a new hydrogen bond may be formed in the composite.
• Example 2 Preparation and identification of hyaluronic acid phospholipid complex 2 1.2 g of sodium hyaluronate and 0.24 g of the resin in Example 1 were accurately weighed (the mass ratio of hyaluronic acid to phospholipid was 1:0.2) The rest of the preparation process is the same as complex 1.
• the method for determining the complexation of phospholipids and hyaluronic acid in complex 2 is the same as that of complex 1, and the mass ratio of phospholipid to hyaluronic acid involved in the complex is 0.1886.
• the identification method of the composite 2 is the same as that of the composite 1, and the change in the infrared spectral absorption characteristics and the thermochemical property is substantially the same as that of the composite 1.
• Wistar rats females weighing 250-280 g, were randomly divided into 4 groups, 8 rats in each group, which were saline (NS) control group, hyaluronic acid experimental group, and mixture (hyaluronic acid and lecithin). The mass ratio was 1: 3) Experimental group and hyaluronic acid phospholipid complex (complex 1 in Example 1) Experimental group. It is administered by intragastric administration at a dose equivalent to 60 mg/kg body weight of hyaluronic acid.
• Rats were fasted (without water) for 12 h before the experiment. They were anesthetized with intraperitoneal injection of pentobarbital sodium, and blood was taken at the subclavian sinus at 0, 1, 2, 4, 7, 10, 12 h after administration. Serum was centrifuged when the serum was precipitated, and the hyaluronic acid concentration in the serum was measured using a hyaluronic acid radioimmunoassay kit.
• Fig. 3 is a time chart of the experimental group and the control group of the present invention, and the present invention has a promoting effect and a sustained release effect on oral absorption of hyaluronic acid.
• the concentration of hyaluronic acid in the serum of the complex group 1 was significantly higher than that of the hyaluronic acid group ( ⁇ 0.05 in the 4-10 h after drug administration) and the NS control group (the corpse ⁇ 0.01) , also higher than the mixture group; and the concentration of hyaluronic acid in the serum of the mixture group was higher than that of the hyaluronic acid group only at a certain time point.
• the transparent shield acid and phospholipid form a complex, can promote the oral absorption of exogenous hyaluronic acid, and can prolong the absorption time, with a sustained release effect.

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• 2005
  • 2005-07-13 CN CNA2005100440676A patent/CN1742623A/zh active Pending
• 2006
  • 2006-07-12 JP JP2008520696A patent/JP5114397B2/ja not_active Expired - Fee Related
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