WO2012122678A1 - 一种鹿茸全成分均一冻干制剂及其生产方法 - Google Patents

一种鹿茸全成分均一冻干制剂及其生产方法 Download PDF

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WO2012122678A1
WO2012122678A1 PCT/CN2011/000427 CN2011000427W WO2012122678A1 WO 2012122678 A1 WO2012122678 A1 WO 2012122678A1 CN 2011000427 W CN2011000427 W CN 2011000427W WO 2012122678 A1 WO2012122678 A1 WO 2012122678A1
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velvet
antler
preparation
freeze
lyophilized
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PCT/CN2011/000427
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English (en)
French (fr)
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董玲
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Dong Ling
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Priority to PCT/CN2011/000427 priority Critical patent/WO2012122678A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/36—Skin; Hair; Nails; Sebaceous glands; Cerumen; Epidermis; Epithelial cells; Keratinocytes; Langerhans cells; Ectodermal cells
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • the present invention relates to a freeze-dried shaped preparation containing a traditional Chinese medicine active ingredient and a method for producing the same, and particularly to a velvet whole ingredient uniform freeze-dried preparation and a production method thereof.
  • Antler is a young horn that is not ossified by male deer.
  • the processing of antler should start from taking the velvet.
  • the velvet antler removed should be washed with water and the blood in the velvet is taken out.
  • the slashing of the snails is also done to reshape the bones to make the shape beautiful.
  • the pilose antler prescribed by the Pharmacopoeia is: the sika velvet medicinal material is divided into two bars and three scorpions.
  • the velvet medicinal herbs are divided into three scorpions and lotus.
  • antler slices are generally divided into four grades, the first flower buds are cut into pieces at the top of the velvet antler, which are called blood tablets; the second is smooth, no sponge-like pores, and the color is waxy and smooth. Wax film; third, because the surface is not uniform, no waxy luster, known as sand, fourth, because the surface has a sponge-like pores, known as bone.
  • the velvet antler “the quality of pure yang, containing the hair of the hair", was listed by the Chinese medicine as the first choice for the “Yangyang”. From the perspective of modern medicine, "Yuanyang” includes basic physiological functions of the human body such as reproduction, growth and metabolism. Deer antler has the functions of refining the marrow, promoting blood and helping the yang, strengthening the muscles and strengthening the bones, and attending all diseases such as deficiency, dizziness, deafness, darkness, impotence, slippery essence, waist and knee weakness, debilitating cold, and uterine bleeding. The clinically used amount is 1. 5 ⁇ 3g, generally no more than 6g.
  • the main purpose of velvet processing is dehydration, drying, anti-corrosion, disinfection, conformal, color retention, quality improvement, and preservation.
  • China's antler processing has been using boiling water boiling and high temperature baking technology.
  • this processing method has great drawbacks. This is because the pharmacological activity of velvet antler is mainly based on the large amount of protein bioactive factors contained in it, and even the addition of white wine can denature the protein. Therefore, the traditional antler processing method causes the active ingredients in the velvet to be affected to varying degrees. Loss and destruction.
  • Growth factor substances such as nerve growth factor, epidermal growth factor, and insulin-like growth factor contained in velvet antler are all protein hormones or polypeptide hormone components, and the high-temperature hot-frying process causes the loss of these active components to be exhausted;
  • freeze-dried antler came into being.
  • the method of freeze-dried antler is to use the theory of modern food and biological products to freeze and dry and combine the structure and biological characteristics of antler to find the body inside the velvet. Free water and structural water are easy to precipitate, so that the fresh velvet is quickly frozen, and then directly sublimed and dehydrated into a high-quality commercial velvet under low-temperature vacuum conditions.
  • the velvet antler obtained by this processing method solves the first problem of the traditional concoction piece, that is, the active preservation factor of the active factor component and other heat sensitive components, but also due to the existence of the structure and shape characteristics of the antler.
  • the second question also exists. From the top to the bottom of the velvet antler, the difference in the different parts of the stalk is difficult to accurately grasp the dose in actual use, resulting in the difference in efficacy and confusion in use, and does not meet the basic requirements for the stable and controllable quality of modern drugs.
  • the freeze-dried shaped preparation is a preparation obtained by applying a suitable auxiliary material during the process by a freeze-drying method.
  • a suitable auxiliary material during the process by a freeze-drying method.
  • Gregory et al. used freeze-drying technology to manufacture high-porosity drug carriers.
  • the carrier disintegrates after saliva in the mouth, without water delivery, giving patients with poor swallowing function and inconvenient water intake. Taking medicine is convenient, and its unique superiority is increasingly favored by patients.
  • the traditional freeze-dried shaped preparation has strict requirements on the excipients, and must have a certain amount of binder and skeleton support agent to form the carrier of the porosity, and the drug loading is limited, and the maximum drug loading per ml is not More than 100 grams. For deer velvet products, 1 to 2 grams, even larger doses, are not useful. Summary of the invention
  • the inventors of the present patent application are determined to advance the problems existing in the prior art, and have been intensively researched and found that the components such as collagen and hyaluronic acid in fresh velvet antler can be further used as a carrier material.
  • the freeze-drying method preserves the activity of active factor components and other heat-sensitive components, and at the same time, obtains a shape, and becomes a uniform preparation of velvet antlers containing various heat-sensitive components.
  • the resulting preparation can be disintegrated in the oral cavity, absorbed by the mucous membrane, and exerts various thermosensitive components, particularly biological factor active ingredients, to complete the present invention.
  • the object of the present invention is to provide a velvet whole ingredient uniform freeze-shaped preparation; another object of the present invention is to provide a preparation method of the velvet whole ingredient uniform freeze-dried preparation.
  • Another object of the present invention is to provide a lyophilized formulation of ginseng, notoginseng, scorpion scorpion, bird's nest, cordyceps, gastrodia elata, ganoderma lucidum, ganoderma lucidum, and the like.
  • a method of preparing the preparation thereof is to provide a lyophilized formulation of ginseng, notoginseng, scorpion scorpion, bird's nest, cordyceps, gastrodia elata, ganoderma lucidum, ganoderma lucidum, and the like.
  • the present invention relates to a velvet whole ingredient uniform freeze-dried preparation, which is prepared by freeze-drying whole antler rot, which is characterized in that it has a fixed form instead of a powder, and contains a whole component of antler, and the preparation of the preparation Vitality index can be
  • the velvet antler is a substance obtained by sika deer or red deer or other suitable deer antler by low temperature freezing, freeze pulverization, and low temperature uniforming.
  • the content of the velvet antler in the whole lyophilized preparation of velvet antler may range from 1-100%, 1-99%, 2-99%, 5-99%, 10-99%, 20-99%, 30 -99%, 1-95%, 2-95%, 5-95%, 10-95%, 20-95%, 30-95%, 1-90%, 2-90%, 5-90%, 10 -90%, 20-90%, 30-90%, 1-80%, 2-80%, 5-80%, 10-80%, 20-80%, 30-80%, preferably 5-100%, It is more preferably from 10 to 100%, particularly preferably from 20 to 100%, and most preferably from 30 to 100%.
  • the velvet whole ingredient uniform freeze-dried preparation of the present invention may contain other Chinese medicinal materials or Chinese herbal medicine extracts and other auxiliary materials, such as various sugars, amino acids and long chains, in addition to the uniform velvet whole ingredients.
  • auxiliary materials such as various sugars, amino acids and long chains, in addition to the uniform velvet whole ingredients.
  • a natural or synthetic high molecular polymer as well as a flavor or flavoring agent.
  • the other Chinese herbal medicine or Chinese herbal medicine extract may be fresh medicine, such as fresh ginseng, fresh American ginseng, fresh Sanqi, fresh glutinous rice, etc., or medicinal herbs, such as raw sun ginseng, raw sun ginseng, red ginseng , ginseng, ginseng, notoginseng, woman's glutinous rice, or extracts of medicinal materials, such as ginseng extract, notoginseng extract, gentiana extract, ginseng total saponin, American ginseng total saponin, panax notoginseng saponins, medlar Glutinous oil, etc., may also be a concentrated concentrate of velvet antler, that is, a concentrate obtained by centrifugation of fresh velvet homogenate.
  • the other Chinese medicinal materials are preferably ginseng, notoginseng, gentiana, bird's nest, cordyceps, gastrodia elata, bear bile, ganoderma lucidum and the like. It may be added to the velvet whole ingredient uniform freezing preparation in a single or compatible form, and the content ranges from 0 to 98%, preferably from 1 to 90 or from 5 to 90%, more preferably from 10 to 80%, particularly preferably from 20 to 70%. Most preferably 30-60%.
  • the sugars are mannitol, sorbitol, maltitol, xylitol, lactitol, erythritol, isomalt, lactose, xylose, raffinose, maltose, glucose, galactose, trehalose Or dextrin or hydroxypropyl cyclodextrin;
  • the saccharide is preferably mannitol, erythritol, maltose, trehalose, most preferably mannitol, and the content of the saccharide in the lyophilized whole ingredient uniform freeze-dried preparation
  • the range is 0-50%, preferably 0. 2-40%, more preferably 0.3-30%, particularly preferably 0.5-30%, most preferably 1-30%
  • the amino acid is a mixture of one or more amino acids having 2 to 12 carbon atoms; the amino acids are: glycine, arginine, serine, valine, alanine, aspartame Amino acid, glutamic acid, hydroxyproline, isoleucine, leucine or phenylalanine. Preferred is glycine.
  • the amino acid is present in the velvet whole ingredient homogeneous freeze-dried shaped formulation in an amount ranging from 0 to 50%, preferably from 2 to 40%, more preferably from 3 to 30%, particularly preferably from 4 to 30%, most preferably from 5 to 30%.
  • the long-chain natural or synthetic hydrazine molecular polymer includes, but is not limited to, pullulan, gelatin, xanthan gum, konjac gum, dextran, seaweed gum, gum arabic, guar gum, agar, hydroxymethyl fiber Naturally derived gums such as carrageenan, pectin, and synthetic macromolecules or polymers such as polyvinylpyrrolidone, carbomer, dextran, and other polypeptides or polysaccharides a mixture; the long-chain natural or synthetic high molecular polymer is preferably pullulan, gelatin or a hydrolyzate thereof.
  • the long-chain natural or synthetic high molecular polymer is contained in the velvet whole ingredient uniform freeze-dried shaped preparation in a range of 0-50%, preferably 2-40%, more preferably 3-30%, particularly preferably 4-30% Most preferably 5-30%.
  • the flavor or flavoring agent includes, but is not limited to, mint flavor, jasmine flavor, longan flavor, chrysanthemum flavor, strawberry flavor, banana flavor, chocolate flavor, peanut flavor, hawthorn flavor, mango flavor, jujube flavor, apricot flavor , sweet-scented osmanthus, pineapple, passion fruit, pomegranate, guava, fig, sesame, egg yolk, tomato, corn, cream, blackcurrant, blueberry, licorice, orange, Grape, lemon, kiwi, caramel, vanilla, cherry, cantaloupe, papaya, apple, papaya, lychee, pear, peach, coffee, tea, milk, etc. a fragrance or a mixture of one or more of the above; 01 ⁇ 5% ⁇ The content may be 0. 01-5%.
  • the preparation method of the velvet whole ingredient uniform lyophilized preparation of the present invention comprises the following steps (the skilled person can appropriately add other steps without departing from the essence of the invention) - [0028] 1. Fresh antler low temperature (0 ⁇ or less) frozen;
  • the frozen particles obtained in the second step are homogenized or homogenized to form a suspension preparation solution, or the frozen particles obtained in the second step are dispersed into purified water or the solution, suspension or solution obtained in the third step.
  • 4 (hereinafter below the TC is homogenized or homogenized by a homogenizer to form a suspension preparation solution;
  • the suspension preparation solution obtained in the fourth step is dispensed into a mold of a suitable volume, and after two steps of pre-freezing and freezing, a whole-component freeze-dried preparation of velvet antler is obtained.
  • the present invention without any teaching in the prior art, creatively proposes that ingredients such as collagen, hyaluronic acid, etc. in fresh velvet antler become carrier materials, and further form a shape by freezing and drying.
  • the present invention is completed by a uniform composition of velvet antler having a fixed morphology rather than a powder.
  • the novel venom full-component uniform preparation formed by the invention effectively preserves the heat-sensitive and sputum active substances in the antler; the form of the preparation enables the absorption of the mucous membrane to ensure the effective absorption and function of the whole component; the uniformity provides It can be used as a basis for preparation and prescription, and provides a new solution to solve the problem of uniformity and controllability of traditional Chinese medicines, especially decoction pieces; among them, ginseng, ginseng, American ginseng, and seven can be added.
  • the velvet whole ingredient lyophilized preparation of the present invention has a vigor index of 10-3, 500 IU/g, and has high vigor.
  • the reason why the vitality index is used to characterize the velvet whole ingredient uniform freeze-dried preparation of the present invention is that it is processed by the antler processing in the past, and if the whole fresh velvet antler is processed by freeze-drying, it is often found that it is better.
  • the invention adopts the activity unit as the quality evaluation index for the active velvet antler, organically combines the advantages of the freeze-drying process with the foundation of the material and the drug effect, and provides conditions and guarantees for optimizing and stabilizing the process and continuously stabilizing the product quality.
  • this innovation does not take into account: there are a large number of active ingredients in the antler that are discarded after the supernatant is taken from the low temperature homogenate, such as hypoxanthine, brain pigment, sialic acid, phospholipids, etc.
  • the liquid fraction is also distributed.
  • the discarding of the non-supernatant fraction has a large amount of other active ingredient loss, and it does not reflect the characteristics of the whole component velvet antler. It has a significant gap with the traditional Chinese medicine under the guidance of traditional Chinese medicine theory.
  • the present invention not only preserves the sensitive component of the cockroach activity, but also retains the whole component of the velvet antler, and is a useful attempt to modernize the traditional Chinese medicine based on the theory of traditional Chinese medicine.
  • the invention also ensures that the deer obtained
  • the quality of velvet products is consistently controllable, industrialized, and meets the requirements of modern laws and regulations for pharmaceutical medicinal materials and health care products, and provides a strong support for Chinese medicine to the world.
  • the obtained preparation is convenient to take, the oral cavity is dissolved, and the viscosity of the raw material stimulated in the unique process can promote the mucoadhesiveness of the velvet antler, and other oral forms such as tablets, capsules, granules, soft capsules and the like.
  • it can increase the absorption through the gastric mucosa, so that the bio-active factors and other heat-sensitive substances protected by the process are not inactivated by the destruction of the gastrointestinal acid, alkali and various enzymes, and the effect of fresh antler is better. . Therefore, the present invention has a better advantageous effect than the prior art. See the examples for specific experimental data. detailed description
  • the frozen granules obtained in the second step are homogenized or homogenized to form a suspension preparation solution, or the frozen granules obtained in the second step are dispersed into purified water or the solution or suspension obtained in the third step. Or in an emulsion, homogenized or homogenized below 40 ° C to form a suspension preparation solution;
  • the suspension preparation solution obtained in the fourth step is dispensed into a mold of a suitable volume, and after two steps of pre-freezing and freezing, a lyophilized whole-component homogeneous freeze-dried preparation is obtained.
  • Example 5 5mg fresh 10mg pullulan lOOmg 0. 05mg thin antler lotus essence
  • Example 6 3mg fresh deer 20mg 2mg hydrolyzed 2mg glycine l OOmg
  • the 1640 medium was added with 10% (ml/ml) calf serum and stored at 4 ° C until use.
  • the 1640 medium was added with 4% (ml/ml) calf serum and stored at 4 ° C until use.
  • a solution of 5. Omg/ml was prepared by using PBS, sterilized by filtration through a 0.22 ⁇ n filter, and placed in a glass or plastic bottle.
  • BALB/C3T3 cell culture medium A sufficient amount of BALB/C3T3 cell culture medium was taken, and BALB/c3T3 cells were collected by centrifugation, washed three times with a complete culture solution, and then resuspended in a complete culture solution to prepare a cell stock solution of 5.0 ⁇ 104 cells/ml. Place at 37 ⁇ l'C for use.
  • a standard was prepared by mixing 1000 IU/ml with sterile water and diluted to 50 IU/ml with complete culture.
  • the cell stock was inoculated into a 96-well cell culture plate at 100 ⁇ l per well. After being cultured for 24 hours under conditions of 37 1 1 ⁇ and 5% C02, the medium was replaced with a maintenance medium, and the mixture was further cultured at 37 ° 1 ° C for 24 hours under 5% CO 2 .
  • the colorimetric value on the microplate reader was measured at a wavelength of 570 nm and a reference wavelength of 630 ⁇ , and the measurement results were recorded.
  • the four-parameter regression calculation method is used to calculate the half-effect dilution multiple of each test product (ie, the dilution factor from the sample solution to be tested to the maximum effect point of 50% of the reference product) and calculate the result according to the following formula. .

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Description

一种鹿茸全成分均一冻干制剂及其生产方法 技术领域
[0001 ] 本发明涉及一种含有中药活性成分的冻干赋形制剂及其生产方法，特别是涉及一 种鹿茸全成分均一冻干制剂及其生产方法。 背景技术
[0002] 鹿茸药用最早见于古代《神农本草经》，李时珍在《本草纲目》中更为详尽地介绍了 鹿茸的炮制方法和药用功效。
[0003] 鹿茸是雄性鹿尚未骨化的幼嫩茸角。鹿茸加工应从取茸开始。取茸方法基本有两 种，一是用锯贴头皮锯下，称锯茸；二是连头盖骨带茸砍下，称砍茸。取下的鹿茸先要用水洗 净,抽出茸内积血。 砍茸还要进行修骨整形，使形状美观。 药典规定的鹿茸为：梅花鹿茸药 材分为二杠、三岔。 马鹿茸药材分为三岔和莲花。
[0004] 市售鹿茸切片一般分为四级,一等花茸片为鹿茸顶端的一段切成，称为血片；第二 等由于切面平滑，无海绵样孔隙，颜色如蜡样光洁，习称蜡片；第三等因为表面不均一,无蜡 样光泽，习称砂片，第四等因为表面有海绵样孔隙，习称骨片。
[0005] 鹿茸"禀纯阳之质，含生发之气"，被中医列为峻补"元阳"的首选药。 从现代医学 观点看，"元阳 "包括了生殖、生长代谢等人体基本生理功能。鹿茸具有生精补髓、益血助阳、 强筋健骨的功能，主治一切虚损、头暈、耳聋、目暗、阳痿、滑精、腰膝无力、虚寒带下、崩漏等 病症。 临床常用量为 1. 5〜3g，一般最多不超过 6g。 现代药理学研究发现，鹿茸具有强心、 提髙机体免疫功能、促进创伤愈合，以及性激素样作用。 鹿茸除在中医处方中使用外，还常 见于滋补类保健品，例如鹿茸精、鹿茸酒、鹿茸胶等等。
[0006] 鹿茸加工的主要目的是脱水、干燥、防腐、消毒、保形、保色，提髙质量，利于保存。 长期以来，我国鹿茸加工一直采用沸水煮炸和高温烘烤技术。 但是这种加工方法存在很大 的缺陷。 这是由于鹿茸的药理学活性的基础主要为其中含有的大量蛋白质类生物活性因 子，而即使加入白酒也会使蛋白质变性，因此传统的鹿茸加工方法造成茸内有效成分活性 物质遭到不同程度的流失和破坏。
[0007] 综上所述，传统鹿茸炮制方法和饮片在实际应用中，存在如下 2个问题：
[0008] (1)鹿茸中含有的神经生长因子、表皮生长因子、类胰岛素样生长因子等生长因子 类物质都是蛋白激素或多肽激素类成分，高温热炸工艺使这些活性成分损失殆尽；
[0009] (2)传统的鹿茸分级是在外观性状上的分级，是定性的，而非定量的，这给医生和 患者用药带来了极大的困惑，各分级鹿茸饮片之间没有换算关系，等量换算会在不同饮片 之间切换时，造成药效的巨大差异。
[0010] 为了解决如上问题，冻干鹿茸应运而生，冻干鹿茸的炮制方法是采用现代食品和 生物制品冷冻保鲜与干燥技术理论，结合鹿茸的组织结构和生物学特性，设法使茸体内的 游离水和结构水易于析出，使鲜茸经速冻后，在低温真空条件下直接升华脱水干燥成优质 商品茸的新工艺。 避免了现行的 "水煮、烘烤 "加工法对鹿茸内热敏活性成分如：酶、蛋白激 素和多肽激素等的破坏；可保持鲜鹿茸的形状、色泽、味道基本不变；并最大限度地保持鹿 茸的营养成分和生理活性成分不流失、不破坏，提高了鹿茸的产品质量和外观性能。
[0011 ] 以这种加工方式获得的鹿茸虽然解决了传统炮制饮片的第 1个问题，即活性因子 类成分和其他热敏感成分活性保存的难题，但是同样因存在鹿茸的组织结构和外形特征， 第 2个问题同样存在。从鹿茸顶部到底部，不同部位饮片的差异，在实际使用中对剂量难以 较为准确的把握,造成疗效的差异和使用中的困惑，也不符合现代药物对质量稳定可控的 基本要求。
[0012] 为了解决如上问题，尝试将冻干鹿茸通过粉碎、混合等工艺，试图获得粉末，或者 将其填入胶囊，成为一种全成分均一饮片或制剂。 但是各级粉碎等工艺过程中的机械力和 产热会极大的破坏活性因子类成分和其他热敏感成分的活性，同时因鹿茸的解剖结构分为 骨部和皮部，骨部在干燥后较易粉碎，而皮部在干燥后，犹如鞣制后的皮革，非常难以粉碎， 往往造成该类物质受热过度,而鹿茸茸皮中含有大量的有效成分，在粉碎过程中损失尤其 巨大.即使采用低温粉碎，也很难将干燥茸皮粉碎到合适粒度。
[0013] 即使在未来，有可能将保鲜鹿茸处理得到保鲜茸粉,其制剂形态所形成的服用方 式也会导致活性因子类成分和其他热敏感成分难以发挥作用，口服粉剂和粉剂填充的胶囊 使活性因子类成分和其他热敏感成分在胃肠道酸碱和各种消化酶的作用下，基本降解,很 难吸收发挥作用。 同时，口服粉剂的口感也很难令人接受。
[0014] 冻干赋形制剂是采用冷冻千燥法，在工艺过程中加以适当的辅料赋形而获得的制 剂。 早期用于制备化学药物， Gregory等采用冷冻干燥技术制造了高孔隙率的药物载体，该 载体在口腔遇到唾液后崩解，不需水送服，给一些吞咽功能不好和取水不便的病人服药提 供了方便，以其独特的优越性越来越受到患者的喜爱。
[0015] 但是传统冻干赋形制剂对辅料有严格的要求，必须具备一定量的粘结剂和骨架支 持剂才能形成髙孔隙率的载体，且载药量有限，每毫升最大载药量不超过 100亳克。对于鹿 茸千品动辄 1至 2克,甚至更大的药量而言，没有用武之地。 发明内容
[0016] 本专利申请的发明人针对现有技术中存在的问题，锐意进取，经过深入地研究出 人意料地发现可以以鲜品鹿茸内的如胶原蛋白、透明质酸等成分成为载体材料，进一步通 过冷冻干燥法保存活性因子类成分和其他热敏感成分的活性，同时获得赋形，成为一种含 有各种热敏性成分在内的鹿茸全成分均一制剂。 产生的制剂可以在口腔内崩解，通过粘膜 吸收,发挥各种热敏性成分，尤其是生物因子类活性成分的作用，从而完成了本发明。
[0017] 本发明目的在于提供一种鹿茸全成分均一冻千赋形制剂；本发明另一目的在于提 供该鹿茸全成分均一冻干赋形制剂的制备方法。
[0018] 本发明的目的还在于提供一种将人参、三七、蛤士蟆、燕窝、虫草、天麻、熊胆、灵芝 等贵细料药材和全成分均一鹿茸配伍的冻干赋形制剂及其所述制剂的制备方法。
[0019] 本发明所述一种鹿茸全成分均一冻干制剂，由完整鹿茸经冷冻干燥制得，其特征 在于其具有固定的形态而非粉体，其中含有鹿茸全成分，并且所述制剂的活力指数可以为
10 - 1000IU/克， 10- 1500IU/克, 10-1800IU/克， 10- 2000IU/克, 10- 2500IU/克， 10-3, 000IU/ 克， 10- 3, 500 I U/ 克， 20- 1000 IU/ 克， 20- 1500IU/ 克， 20- 1800 IU/ 克， 20- 2000 IU/ 克， 20 - 2500IU/克， 20- 3000IU/克， 20- 3， 500IU/克， 30- 1000IU/克， 30- 1500IU/克， 30- 1800IU/ 克， 30- 2000IU/克， 30- 2500IU/克， 30- 3000IU/克， 30-3500IU/克 (以 2005年版药典附录 XH重组人表皮生长因子生物学活性测定法细胞增殖 /MTT比色法测定），优选 10-3, 000 IU/ 克，特别优选 20-2500IU/克。
[0020] 所述鹿茸全成分为梅花鹿或马鹿或其它合适的鹿的完整鹿茸经低温冷冻、冷冻 粉碎、低温匀桨后得到的物质。 所述鹿茸全成分在鹿茸全成分均一冻干制剂中的含量范 围可以为 1-100 % , 1-99 %， 2-99 %， 5-99 %， 10-99 %， 20-99 %， 30-99 % , 1-95 %， 2-95 %， 5-95 % , 10-95 %， 20-95 % , 30-95 %， 1-90 %， 2-90 %， 5-90 %， 10-90 %， 20-90 % , 30-90 %， 1-80 % , 2-80 % , 5-80 %， 10-80 %， 20-80 %， 30-80 %，优选 5-100 %，更加优选 10-100 % ,特 别优选 20- 100%，最优选 30-100%。
[0021 ] 本发明的鹿茸全成分均一冻干赋形制剂中除含有均一的鹿茸全成分外，还可以含 有其它中药材或中药材提取物以及其他辅料,例如各种糖类、氨基酸、长链天然或合成高分 子聚合物以及香精或矫味剂。
[0022] 所述其它中药材或中药材提取物可以为鲜药材，如鲜人参、鲜西洋参、鲜三七、鲜 蛤士蟆等，或药材饮片，如生晒参、生晒西洋参、红参、高丽参、糖参、三七、蛤士蟆，或药材的 提取物，如人参提取物、三七提取物、蛤士蟆提取物、人参总皂苷、西洋参总皂苷、三七总皂 苷、蛤士蟆油等，还可以是鹿茸的活性浓縮物，即鲜鹿茸匀浆离心后得到的上清液的浓縮 物。 所述其它中药材优选人参、三七、蛤士蟆、燕窝、虫草、天麻、熊胆、灵芝等。 其可以以 单一或者配伍形式加入到鹿茸全成分均一冻千制剂中，含量范围为 0-98 %，优选 1-90或 5-90%，更加优选 10- 80 % ,特别优选 20- 70 % ,最优选 30-60%。
[0023] 所述糖类为甘露醇、山梨醇、麦芽糖醇、木糖醇、乳糖醇、赤藓糖醇、异麦芽糖醇、乳 糖、木糖、棉籽糖、麦芽糖、葡萄糖、半乳糖、海藻糖、糊精或羟丙基环糊精；所述糖类优选甘 露醇、赤藓糖醇、麦芽糖、海藻糖，最优选甘露醇，所述糖类在鹿茸全成分均一冻干赋形制 剂的含量范围为 0-50 %，优选 0. 2-40 %，更加优选 0. 3-30 %，特别优选 0. 5-30 %，最优选 1-30%
[0024] 所述氨基酸为具有 2个至 12个碳原子的氨基酸的一种或一种以上的混合物；所 述氨基酸为：甘氨酸、精氨酸、丝氨酸、脯氨酸、丙氨酸、天冬氨酸、谷氨酸、羟脯氨酸、异亮氨 酸、亮氨酸或苯丙氨酸。 优选为甘氨酸。 所述氨基酸在鹿茸全成分均一冻干赋形制剂中的 含量范围为 0-50 %，优选 2-40 %，更加优选 3-30 %，特别优选 4-30 %，最优选 5-30 %。
[0025] 所述长链天然或合成髙分子聚合物包括但不限于普鲁兰、明胶、黄原胶、魔芋胶、 右旋糖酐、海藻胶、阿拉伯胶、瓜儿豆胶、琼脂、羟甲基纤维素、角叉菜胶、果胶等天然来源胶 类和合成高分子化合物或聚合物如聚乙烯吡咯垸酮、卡波姆、葡聚糖以及其他多肽或多糖 中的任一种或数种的混合物；所述长链天然或合成高分子聚合物优选普鲁兰、明胶及其水 解物。所述长链天然或合成高分子聚合物在鹿茸全成分均一冻干赋形制剂中的含量范围为 0-50 % ,优选 2-40 %，更加优选 3-30 % ,特别优选 4-30 %，最优选 5-30 %。
[0026] 其中所述香精或矫味剂包括但不限于薄荷味、茉莉味、桂圆味、菊花味、草莓味、香 蕉味、巧克力味、花生味、山楂味、芒果味、枣味、杏味、桂花味、菠萝味、西番莲味、石榴味、番 石榴味、无花果味、芝麻味、蛋黄味、番茄味、玉米味、奶油味、黑加仑味、蓝莓味、甘草味、橙 味、葡萄味、柠檬味、猕猴桃味、焦糖味、香草味、樱桃味、哈密瓜味、木瓜味、苹果味、番木瓜 味、荔枝味、梨味、桃味、咖啡味、茶味、牛奶味等的香精或以上一种或几种香味的混合物；其 含量可以是 0. 01-5%。
[0027] 本发明的鹿茸全成分均一冻干制剂的制备方法包括以下步骤（本领域技术人员 在不背离本发明实质的前提下，可以适当再加入其它步骤） - [0028] 1. 新鲜鹿茸低温（0Ό以下）冷冻；
[0029] 2. 冷冻的鹿茸， 40Ό以下粉碎成冷冻的颗粒（粒径 20目左右） ；
[0030] 3. 纯化水中加入适量含有人参、三七、蛤士蟆、燕窝、虫草、天麻、熊胆、灵芝等药材 或其提取物,加或不加各种糖类、氨基酸、长链天然或合成高分子聚合物，加或不加香精或 矫味剂，混合溶解分散后降至低温 40°C以下；
[0031 ] 4. 第 2步得到的冷冻颗粒 40Ό以下均质或匀浆形成混悬配制液，或将第 2步得到 的冷冻颗粒分散入纯化水或者第 3步得到的溶液、悬浊液或乳浊液中，4(TC以下以均质乳 化机均质或匀浆形成混悬配制液；
[0032] 5. 第 4步得到的混悬配制液，分装至合适体积的模具，经预冻和冷冻千燥两个工 艺步骤后得到鹿茸全成分均一冻干赋形制剂。
[0033] 本发明在现有技术没有任何教导的情况下，创造性地提出以鲜品鹿茸内的如胶原 蛋白、透明质酸等成分成为载体材料，进一步通过冷冻千燥法赋形，获得了一种具有固定的 形态而非粉体的鹿茸全成分均一制剂,从而完成了本发明。 本发明所形成的全新的鹿茸全 成分均一制剂，有效保存了鹿茸中的热敏、髙活性物质；其制剂形态使粘膜吸收得以实现， 保证全成分的有效吸收并发挥作用；其均一性提供了可供调剂和处方使用物质基础，同时 为解决中药，尤其是饮片，质量均一和可控的难题提供了一种新的解决方式；其中可加入参 (人参、髙丽参、西洋参）、七（三七）、哈士蟆、燕窝、虫草、天麻、熊胆、灵芝等贵细料药材和 提取物，使得中药的配伍使用提高到更高的水平。 并改变了用药时的口感和依从性。
[0034] 此外，本发明鹿茸全成分均一冻干制剂的活力指数为 10-3, 500IU/克，活力较高。 之所以采用活力指数来表征本发明的鹿茸全成分均一冻干赋形制剂是由于以往的鹿茸加 工炮制，如果是对整支的鲜鹿茸采用冷冻干燥的方法进行加工处理，往往发现有更好的药 理效果，但是对这种生物效果的物质表征只是以："在某个分子量范围处，发现有大量蛋白， 或者是水溶性的总蛋白量增加量为多少。"在物质基础和药效活性之间，没有建立起必然的 联系，对质量均一和质量控制而言，也没有评价和控制的指标。本发明采用活性单位作为对 活性鹿茸的质量评价指标，有机地将冷冻干燥工艺的优势和物质与药效的基础统一起来， 为优化和稳定工艺、持续稳定产品质量提供了条件和保障。
[0035] 此外，文献报道，冻干鹿茸水提物促大鼠成骨样细胞增殖活性（MTT法） 高达 245. 25%，是传统热炸鹿茸的 2. 2倍；IGF_I分泌量也高达 66. 3ng/ml，是热炸茸的 1. 2倍； 抑制肝癌细胞活性为 47. 64%，是热炸茸的 1. 4倍。所以很多方法都是将鲜鹿茸低温匀浆后 取上清液冻干替代鹿茸入药。
[0036] 但是这种创新没有考虑到：低温匀浆取上清液后被抛弃的鹿茸中还有大量的有效 成分，如：次黄嘌呤、脑素、唾液酸、磷脂等是在非上清液部分也有分布的，丢弃非上清液部 分则有大量其他有效成分损失，而且不能反映全成分鹿茸的特点，与传统中医药理论指导 下的中药用药有着比较显著的差距。
[0037] 所以本发明，不但保存了髙活性的敏感性成分，也保留了鹿茸的全成分,是以中医 药理论为体，以现代科学手段为用的中药现代化的有益尝试。 该发明还能够保证所获得鹿 茸产品的质量持续均一可控，能够产业化，并满足现代法律法规对药物药材和保健品的要 求,对中药走向世界提供了一种强有力的支持方式。
[0038] 同时，所获得的制剂服用方便，口腔崩溶，独特工艺中激发的原料粘性可以促进鹿 茸的粘膜黏附性，与其他如片剂、胶囊剂、颗粒剂、软胶囊剂等口服形态相比，可增加通过胃 前粘膜产生的吸收，使工艺保护的生物活性因子和其他热敏性物质不会受到胃肠道酸碱、 多种酶类的破坏而失活,更好的发挥鲜鹿茸的功效。 因此本发明相对于现有技术具有较好 的有益效果。 具体实验数据参见实施例。 具体实施方式
[0039] 以下通过实施例进一步详细地说明本发明，但这些实施例只是本发明的举例，本 发明并不仅限于此。
[0040] 根据表 1所示的成分及其数量制备鹿茸全成分均一制剂，其具体方法如下： [0041 ] 1. 新鲜鹿茸低温（0摄氏度以下）冷冻；
[0042] 2. 冷冻的鹿茸， 40摄氏度以下粉碎成冷冻的颗粒（粒径 20目左右） ；
[0043] 3. 纯化水中加入适量含有人参、三七、蛤士蟆、燕窝、虫草、天麻、熊胆、灵芝等药材 或其提取物，加或不加各种糖类、氨基酸、长链天然或人工高分子聚合物，加或不加香精或 矫味剂,混合溶解分散后降至 4(TC以下；
[0044] 4. 第 2步得到的冷冻颗粒 40 Ό以下均质或匀浆形成混悬配制液，或将第 2步得到 的冷冻颗粒分散入纯化水或者第 3步得到的溶液、悬浊液或乳浊液中，40 °C以下均质或匀 浆形成混悬配制液；
[0045] 5. 第 4步得到的混悬配制液，分装至合适体积的模具，经预冻和冷冻千燥两个工 艺步骤后得到鹿茸全成分均一冻干赋形制剂。
[0046] 表 1 ：
[0047]
Figure imgf000006_0001
全成分均 贵细 糖类 长链高分子 難 纯化水 其他辅料 一鹿 药材 聚合物 实施例 3 lOOmg鲜 200mg 50mg 0. 05mg金 鹿茸 鲜西 帝巧克力 洋参 香精，
0. 05mg薄 荷香精 实施例 4 12mg鲜鹿 50mg 4mg lOOmg 0. 05m 人 高丽 甘露 参香精 参提 醇
取物 实施例 5 150mg鲜 10mg普鲁兰 lOOmg 0. 05mg薄 鹿茸 荷香精 实施例 6 3mg鲜鹿 20mg 2mg水解明 2mg甘氨 l OOmg
茸 三七 胶 酸 总皂
苷 实施例 7 300mg鲜 40mg普鲁兰 300mg lmg金帝巧 鹿驾 克力香精， lmg薄荷香 精， lm 安 赛蜜
[0048]
[0049] 注：甘氨酸：北京精求化工有限责任公司，
[0050] 甘露醇：北京精求化工有限责任公司
[0051 ] 薄荷醇：苏州禾田香料有限公司
[0052] 安赛蜜：张家港浩波化学品有限公司
[0053] 实验例
[0054] 实施例 1-8制备的鹿茸全成分均一制剂的活性测定
[0055] 测定方法釆用 2005年版中国药典附录 XH重组人表皮生长因子生物学活性 [0056] 测定法细胞增殖 /MTT比色法
[0057] 1实验材料
[0058] 1. 1RPMI 1640培养液
[0059] 每 1000ml加 2. 2g碳酸氢钠， 4Ό保存待用。
[0060] 1. 2完全培养液
[0061 ] 1640培养液添加 10% (ml/ml)小牛血清， 4°C保存待用。
[0062] 1. 3维持培养液
[0063] 1640培养液添加 4% (ml/ml)小牛血清， 4°C保存待用。
[0064] 1. 4PBS
[0065] 取 8g氯化钠、0. 2g氯化钾、1. 44g磷酸氢二钠、 0. 24g磷酸二氢钾加蒸馏水配制成 1000ml的溶液 121 °C 15min灭菌。
[0066] L 5噻唑兰 MTT溶液
[0067] 用 PBS配制成 5. Omg/ml的溶液，经 0. 22 μ tn滤膜过滤除菌，置于玻璃或塑料瓶中，
4 Ό避光保存。
[0068] 1. 6裂解液
[0069] 二甲亚砜（DMS0，分析纯）
[0070] 1. 7BALB/c3T3细胞株
[0071 ] 传代后 48小时用于效价测试。
[0072] 1. 8rh EGF活性测定用标准品
[0073] 2试验步骤
[0074] 以下 2. 1〜 2. 9步骤均需在无菌条件下进行。
[0075] 2. 1试验准备
[0076] 将试验所用溶液预温至 37土 。
[0077] 2. 2制备细胞原液
[0078] 取足量的 BALB/C3T3细胞培养液，离心收集 BALB/c3T3细胞，用完全培养液洗涤三 次，然后重悬于完全培养液配制成 5. 0 X 104个细胞 /ml的细胞原液，置于 37 ± l'C备用。
[0079] 2. 3标准品溶液
[0080] 取一支标准品用无菌水配制成 1000IU/ml，用完全培养液稀释至 50IU/ml。
[0081 ] 2. 4样品溶液
[0082] 将实施例 1-7制备的产品用无菌水溶解后，待测。
[0083] 2. 5稀释度的测定
[0084] 在 96孔细胞培养板中，对标准品、样品溶液以 4倍系列稀释，参考品和样品同做 8 个稀释度,每个梯度做 2个复孔。
[0085] 2. 6加入细胞原液并培养
[0086] 取细胞原液接种于 96孔细胞培养板中，每孔 100 μ 1。 置于 37土 1 Ό， 5% C02条件 下培养 24小时后，换成维持培养液,继续置于 37士 1 °C , 5% C02条件下培养 24小时。
[0087] 2. 7加入样品及标准品溶液培养
[0088] 制备的细胞培养板弃去维持液，加入标准品及样品溶液，每孔 100 μ 1。 置于 37士 1°C , 5 % C02条件下培养 66〜 72小时。 [0089] 2. 8加入 MTT溶液并培养
[0090] 每孔加入 20 μ 1 MTT溶液，置 37 °C , 5 % C02培养 4h-6h。
[0091 ] 2. 9加入裂解液
[0092] 弃去培养板中的液体，每孔加入 100 μ 1裂解液，混匀溶解。
[0093] 2. 10测定吸光度值
[0094] 在酶标仪上比色，测定波长 570nm，参比波长 630ηπι，记录测定结果。
[0095] 2. 1 1结果计算
[0096] 用四参数回归计算法进行处理，分别计算各待检品的半效稀释倍数（即从待检样 本溶液至相当于参考品 50 %最大效应点的稀释倍数）并按下式计算结果。
_ _ D, H,
[0098] 式中： T1 样品效价， IU
[0099] TO ……标准品效价， IU
[0100] D1 · •… 样品预稀释倍数
[0101 ] DO •… 标准品预稀释倍数
[0102] HI 一…样品半效稀释倍数
[0103] HO …，标准品半效稀释倍数
[0104] 活性测定结果：
[0105]
Figure imgf000009_0001
[0106]
[0107] 应该注意的是，本领域技术人员对于本发明的各种细节可以进行各种的修改，但 毫无疑问，这些修改都将落入本发明的保护范围之内。

Claims

1. 一种鹿茸全成分均一冻干制剂，由完整鹿茸经冷冻千燥制得，其特征在于其具有固 定的形态而非粉体，其中含有鹿茸全成分，所述鹿茸全成分在鹿茸全成分均一冻干制剂中 的含量范围为 1-100 %，并且所述制剂的活力指数为 10-3500IU/克,所述活力指数以 2005 年版中国药典附录 XH重组人表皮生长因子生物学活性测定法测定。
2. 如权利要求 1所述的冻干制剂,其特征在于还含有其它中药材或中药材提取物。
3. 如权利要求 2所述的冻干制剂，其特征在于所述其它中药材为人参、三七、蛤士蟆、 燕窝、虫草、天麻、熊胆、灵芝中的一种或一种以上，所述中药材提取物为人参提取物、三七 提取物、蛤士蟆提取物、鹿茸的活性浓缩物中的一种或一种以上。
4. 如权利要求 1-3任一项所述的冻干制剂,其特征在于还含有各种糖类、氨基酸、长链 天然或合成高分子聚合物、香精和 I或矫味剂。
5. 如权利要求 4所述的冻干片，其特征在于所述糖类为甘露醇、山梨醇、麦芽糖醇、木 糖醇、乳糖醇、赤藓糖醇、异麦芽糖醇、乳糖、木糖、棉籽糖、麦芽糖、葡萄糖、半乳糖、海藻糖、 糊精或羟丙基环糊精中的一种或一种以上。
6.如权利要求 4或 5所述的冻千片，其特征在于所述氨基酸为甘氨酸、精氨酸、丝氨酸、 脯氨酸、丙氨酸、天冬氨酸、谷氨酸、羟脯氨酸、异亮氨酸、亮氨酸或苯丙氨酸中的一种或一 种以上。
7. 如权利要求 4-6任一项所述的冻干片，其特征在于所述长链天然或合成高分子聚合 物为选自普鲁兰、明胶、黄原胶、魔芋胶、右旋糖酐、海藻胶、阿拉伯胶、瓜儿豆胶、琼脂、羟甲 基纤维素、角叉菜胶、果胶中的一种或一种以上的天然来源胶类和选自聚乙烯吡咯烷酮、卡 波姆、葡聚糖中的一种或一种以上的合成高分子聚合物。
8. 如权利要求 1-7任意一项所述的冻干片的制备方法,包括以下步骤 -
(1)新鲜鹿茸 0摄氏度以下冷冻 ·'
(2)冷冻的鹿茸, 40摄氏度以下粉碎成冷冻的颗粒，所述颗粒的粒径 20目左右；
(3)纯化水中加入适量含有人参、三七、蛤士蟆、燕窝、虫草、天麻、熊胆、灵芝等药材或 其提取物，加或不加各种糖类、氨基酸、长链天然或人工高分子聚合物，加或不加香精或矫 味剂，混合溶解分散后降温至 40'C以下；
(4)第 2步得到的冷冻颗粒 40Ό以下均质或匀浆形成混悬配制液，或将第 2步得到的 冷冻颗粒分散入纯化水或者第 3步得到的溶液、悬浊液或乳浊液中，4(TC以下均质或匀浆 形成混悬配制液；
(5)第 4步得到的混悬配制液，分装至合适体积的模具，经预冻和冷冻干燥两个工艺步 骤后得到鹿茸全成分均一冻千赋形制剂。
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CN103223032A (zh) * 2013-04-30 2013-07-31 布焕景 一种治疗后背大脊梁空痛症的中药组合物
CN103876163A (zh) * 2014-04-01 2014-06-25 吉林大学 一种林蛙肉复合蛋白粉及其制备方法
CN104382972A (zh) * 2014-11-21 2015-03-04 江苏鹏鹞药业有限公司 一种蝙蝠蛾拟青霉菌、人参和三七组合物及其制备方法
CN108079034A (zh) * 2018-02-07 2018-05-29 云南金不换生物科技有限责任公司 冻干三七超微粉的制备方法及其产品
CN108578455A (zh) * 2018-02-07 2018-09-28 云南金不换生物科技有限责任公司 新鲜三七的冻干加工方法及其产品
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CN103070923A (zh) * 2013-01-23 2013-05-01 广州铁路职业技术学院 治疗胃病的药酒及其制备方法
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CN103876163A (zh) * 2014-04-01 2014-06-25 吉林大学 一种林蛙肉复合蛋白粉及其制备方法
CN104382972A (zh) * 2014-11-21 2015-03-04 江苏鹏鹞药业有限公司 一种蝙蝠蛾拟青霉菌、人参和三七组合物及其制备方法
US11452693B2 (en) 2017-07-12 2022-09-27 Conopco, Inc. Freeze dried active composition and a system for using the same
US11730685B2 (en) 2017-07-12 2023-08-22 Conopco, Inc. Skin composition booster oil
CN108079034A (zh) * 2018-02-07 2018-05-29 云南金不换生物科技有限责任公司 冻干三七超微粉的制备方法及其产品
CN108578455A (zh) * 2018-02-07 2018-09-28 云南金不换生物科技有限责任公司 新鲜三七的冻干加工方法及其产品

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