WO2022028084A1 - Solid dispersion for treating cervical spondylosis and use thereof in preparation of sustained-release preparation - Google Patents

Solid dispersion for treating cervical spondylosis and use thereof in preparation of sustained-release preparation Download PDF

Info

Publication number
WO2022028084A1
WO2022028084A1 PCT/CN2021/098700 CN2021098700W WO2022028084A1 WO 2022028084 A1 WO2022028084 A1 WO 2022028084A1 CN 2021098700 W CN2021098700 W CN 2021098700W WO 2022028084 A1 WO2022028084 A1 WO 2022028084A1
Authority
WO
WIPO (PCT)
Prior art keywords
solid dispersion
filtrate
cervical spondylosis
sustained
preparation
Prior art date
Application number
PCT/CN2021/098700
Other languages
French (fr)
Chinese (zh)
Inventor
刘杰
郝洪慧
潘瑞雪
高超
张亚欣
陈克欣
江玉娟
许敏
王莉
Original Assignee
山东明仁福瑞达制药股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 山东明仁福瑞达制药股份有限公司 filed Critical 山东明仁福瑞达制药股份有限公司
Publication of WO2022028084A1 publication Critical patent/WO2022028084A1/en

Links

Images

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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/236—Ligusticum (licorice-root)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/237—Notopterygium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/488—Pueraria (kudzu)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/66—Papaveraceae (Poppy family), e.g. bloodroot
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A61K36/716—Clematis (leather flower)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention belongs to the technical field of sustained-release preparations of traditional Chinese medicines, and in particular relates to a solid dispersion for treating cervical spondylosis and the application of the solid dispersion in the preparation of sustained-release preparations.
  • Cervical spondylosis is a common multiple degenerative disease. It affects 25% of people around the age of 50, 50% at the age of 60, and 80% to 90% after the age of 79.
  • cervical spondylosis include cervical spondylosis, radiculopathy, cervical spondylosis myelopathy, vertebral artery cervical spondylosis, sympathetic cervical spondylosis, and esophageal compression cervical spondylosis.
  • nerve root injury is the type with the highest incidence in cervical spondylosis, accounting for 60% of cervical spondylosis.
  • cervical disc degeneration Because the disease is usually preceded by cervical disc degeneration, and on the basis of intervertebral foramen stenosis, the nerve roots are mechanically compressed and chemically stimulated, resulting in congestion, edema and inflammation.
  • Traditional Chinese medicine classifies cervical radiculopathy as a Blood stasis and qi stagnation and choroidal obstructive disease belong to the category of "arthritis”.
  • Jingtong Granule is an oral traditional Chinese medicine compound preparation for radiculopathy of cervical spondylosis.
  • the traditional Chinese medicine compound includes Panax notoginseng, Sichuan peony root, Corydalis japonica, Pueraria lobata, Weilingxian, and Qianghuo.
  • Panax notoginseng and Chuan peony are the monarch medicines, which can promote blood circulation and improve recovery, promote qi and relieve pain
  • Panax notoginseng is an essential medicine for bone injuries. According to the literature, Panax notoginseng can transform the fatigue and blood of the bone marrow, and prevent the marrow from going out of the bone.
  • Neck pain products currently on sale include Neck Pain Granules, Neck Pain Capsules and Neck Pain Tablets. Since the granules have a heavy taste when taken, capsules and tablets can effectively overcome this defect. However, in order to ensure the effective dose of drugs, especially to effectively relieve the persistent pain symptoms of severe patients, the dosage of tablets and capsules is relatively large. Neck Pain Tablets are 4 tablets each time, three times a day, while Neck Pain Capsules need to be taken once a day. Five capsules, three times a day. In view of this situation, providing the sustained-release preparation of the neck passage product can effectively reduce the number of administrations. Multi-component is an important characteristic of traditional Chinese medicine preparations.
  • the multi-component synchronous release technology of oral traditional Chinese medicine mainly includes multi-layer tablet technology, multi-positioned drug release technology, multi-timed technology, osmotic pump technology, solid dispersion technology, etc. From the perspective of dosage form, it can be divided into matrix-type sustained-release preparations, membrane-controlled sustained-release preparations and osmotic pump-type sustained-release preparations. Among them, matrix sustained-release preparations are a common sustained-release dosage form. technology, the preparation process is simple, and the industrial production is easy.
  • the object of the present invention is to provide a slow-release preparation for a neck pain product, by optimizing the preparation process and auxiliary materials of the existing neck pain series products, to provide a slow, sustained and long-acting release preparation dosage form, reducing the number of patients taking medication.
  • a solid dispersion for cervical spondylosis is provided, and the preparation method of the solid dispersion is as follows: mixing Panax notoginseng powder and ethyl cellulose to obtain a notoginseng-ethyl cellulose combination;
  • the volatile oil and beta cyclodextrin are extracted from the Qiang Huo and Wei Lingxian to obtain an inclusion compound, and the remaining medicinal materials are decocted and filtered to obtain a filtrate;
  • Pueraria lobata and Radix Paeoniae Alba are boiled with water and concentrated, add ethanol, stir and filter to obtain a filtrate part, mix the ethanol extracts of the Radix Radix et Rhizoma, Wei Lingxian filtrate, Pueraria Root, Radix Paeoniae Alba filtrate, Chuanxiong Radix, and Corydalis Rhizoma to obtain a mixed filtrate, remove all the filtrate.
  • the solvent of the mixed filtrate obtains a clear paste, and the clear paste and magnesium oxide are mixed and pulverized to obtain a solid combination;
  • the solid dispersion is obtained by uniformly mixing the notoginseng-ethylcellulose combination, the inclusion compound and the solid combination.
  • Panax notoginseng as a valuable medicinal material, is usually crushed and directly used as medicine to retain all the medicinal parts.
  • the main active ingredient in Panax notoginseng the total saponins of Panax notoginseng, is also of great significance for exerting the effect of promoting blood circulation and removing blood stasis.
  • the present invention firstly pulverizes it into fine powder or ultrafine powder to increase the total amount of total saponins dissolved in Panax notoginseng.
  • ethyl cellulose is used as an auxiliary dispersant, ethyl cellulose It also has good stability under acidic conditions.
  • the sustained release agent for oral preparations, it can well achieve the sustained release effect of total saponins from Panax notoginseng, which is almost close to the first-order kinetic release effect.
  • the research of the present invention also found that by using the combination of ethyl cellulose and magnesium oxide, the volatile oil, clear paste and Panax notoginseng saponins in the solid dispersion can achieve a basically synchronous release effect.
  • the index components of Panax notoginseng saponins and ginseng total saponins can achieve good long-acting and slow-release effects and improve bioavailability.
  • the second aspect of the present invention provides the application of the solid dispersion for treating cervical spondylosis described in the first aspect in the preparation of an anti-cervical spondylosis sustained-release preparation.
  • the solid dispersion provided by the present invention achieves a good slow-release effect of the index components by simply improving the preparation process of the existing neck pain granules, the release effect is close to the first-order kinetic release effect, and the release time can reach 12h , the total release is also significantly better than existing drugs.
  • the solid dispersion preparation has good stability and processing performance, and has good development potential when applied to the preparation of tablets, capsules and other solid dosage forms, and is expected to be a substitute product for the existing neck pain series products.
  • Fig. 1 is a graph of in vitro drug release performance in Example 9;
  • Fig. 1A is a graph showing the in vitro release curve of notoginsenoside Rg1 in the preparations described in Example 1 and Comparative Examples 1-3;
  • Figure 1B is a graph showing the in vitro release curve of notoginsenoside Rg1 in the preparations described in Examples 1-4;
  • FIG. 1C is a graph showing the in vitro release profiles of the three indicator components in the solid dispersion described in Example 1.
  • the present invention proposes a sustained-release preparation for treating cervical spondylosis in view of the drawbacks of the existing neck pain granules that are taken frequently.
  • the first aspect of the present invention provides a solid dispersion for treating cervical spondylosis, and the preparation method of the solid dispersion is as follows: mixing Panax notoginseng powder and ethyl cellulose to obtain a notoginseng-ethyl cellulose combination;
  • Pueraria lobata and Radix Paeoniae Alba are boiled with water and concentrated, add ethanol, stir and filter to obtain a filtrate part, mix the ethanol extracts of the Radix Radix et Rhizoma, Wei Lingxian filtrate, Pueraria Root, Radix Paeoniae Alba filtrate, Chuanxiong Radix, and Corydalis Rhizoma to obtain a mixed filtrate, remove all the filtrate.
  • the solvent of the mixed filtrate obtains a clear paste, and the clear paste and magnesium oxide are mixed and pulverized to obtain a solid combination;
  • the solid dispersion is obtained by uniformly mixing the notoginseng-ethylcellulose combination, the inclusion compound and the solid combination.
  • the mass ratio of the Panax notoginseng, Qianghuo, Weilingxian, Puerariae, Baishao, Chuanxiong and Corydalis is 35-38:100:100:95:95:80-85:60-65.
  • the Panax notoginseng powder is micro powder or superfine powder, and the mesh number is 200 mesh and above.
  • the addition ratio of the Panax notoginseng powder to ethyl cellulose is 1:0.5-0.7.
  • Panax notoginseng as a valuable medicinal material, is usually crushed and directly used as medicine to retain all the medicinal parts.
  • the main active ingredient in Panax notoginseng the total saponins of Panax notoginseng, is also of great significance for exerting the effect of promoting blood circulation and removing blood stasis.
  • the present invention firstly pulverizes it into fine powder or ultrafine powder to increase the dissolution effect of the total saponins of Panax notoginseng.
  • Cellulose also has good stability under acidic conditions and has gel properties, which can well achieve the sustained release effect of Panax notoginseng total saponins, which is almost close to the first-order kinetic release effect.
  • the research of the present invention also finds that under the cooperative action of ethyl cellulose and magnesium oxide, the volatile oil, clear paste and Panax notoginseng saponins in the solid dispersion can achieve a basically synchronous release effect.
  • the notoginseng and ethyl cellulose are mixed by ball milling; further preferably, the mixing speed of the ball milling is 80-120 r/min, and the time is 0.4-0.5 h.
  • the volatile oil is packaged by betacyclodextrin under the action of steam and stirring.
  • the inclusion compound preparation method adopts the method described in paragraph [0010] of patent CN104887771A for inclusion, and the inclusion rate is stable at 85-90%.
  • the medicinal materials obtained from the extraction of volatile oil from Qianghuo and Weilingxian are decocted with water for 2 to 4 times, and the decoctions of several times are combined and filtered to obtain the filtrate.
  • the pueraria root and Radix Paeoniae Alba are boiled in water and then concentrated, and then added with ethanol to stir and filter to obtain the filtrate.
  • the specific steps are as follows: decocting the Radix Puerariae and the Radix Paeoniae Alba in water for 2 to 4 times, and combining and filtering the decocted liquids for several times to obtain the filtrate , the filtrate is concentrated to a density of 1.10-1.15, ethanol is added to the concentrated filtrate until the ethanol concentration in the solution reaches 60-70%, and the filtrate is obtained by filtration after stirring.
  • the preparation method of the alcohol extract of Chuanxiong and Corydalis is as follows: adding ethanol to Chuanxiong and Corydalis for 2 to 4 times of reflux extraction, merging the refluxed extracts for several times, and filtering to obtain a filtrate.
  • the mixed solution is obtained by mixing the Qianghuo, Weilingxian filtrate, Pueraria lobata filtrate, and the alcohol extracts of Chuanxiong and Corydalis Fructus, and heating and stirring for a period of time under water bath conditions.
  • the temperature of the water bath is 45-50°C.
  • the water bath time is 3-3.5h.
  • the mixed filtrate is distilled under reduced pressure to remove part of the solvent and ethanol in the solvent, and then dried to obtain the clear paste.
  • the vacuum degree of the vacuum distillation is -0.03 ⁇ -0.07MPa.
  • the drying method includes, but is not limited to, spray drying, vacuum drying or freeze drying.
  • the clear paste after removing the solvent to obtain the clear paste, it further includes a step of drying the clear paste, and the drying is performed at 40-45°C.
  • the mass ratio of the clear paste to magnesium oxide is 1:0.01-0.02.
  • the mixing mode of the clear paste and magnesium oxide is as follows: the weighed magnesium oxide is added to the clear paste in batches and pulverized by a pulverizer.
  • the solid conjugate, the notoginseng-ethyl cellulose conjugate and the volatile oil inclusion complex are uniformly mixed by ball milling.
  • the rotation speed of the ball mill is 100-130r/min, and the time is 1-1.5h.
  • the second aspect of the present invention provides the application of the solid dispersion for treating cervical spondylosis described in the first aspect in the preparation of an anti-cervical spondylosis sustained-release preparation.
  • the anti-cervical spondylosis sustained-release preparation is an oral dosage form
  • the oral dosage form includes, but is not limited to, granules, tablets, capsules, powders, pills, and the like.
  • the anti-cervical spondylosis sustained-release preparation includes the solid dispersion described in the first aspect and pharmaceutically necessary excipients.
  • the anti-cervical spondylosis sustained-release preparation is a tablet, and the tablet includes the solid dispersion described in the first aspect, and also includes a binder and a lubricant.
  • the lubricant includes, but is not limited to, one or a mixture of modified starch, sodium stearate, and magnesium aluminosilicate.
  • the adhesive includes but not limited to one or a combination of tragacanth, chitosan, alginic acid, and sodium alginate.
  • the tablet includes the solid dispersion described in the first aspect, modified starch and magnesium stearate.
  • the tablet includes the solid dispersion described in the first aspect, alginic acid, modified starch and magnesium stearate.
  • the tablet includes the solid dispersion of the first aspect, alginic acid, microcrystalline cellulose and magnesium aluminum silicate.
  • the anti-cervical spondylosis sustained-release preparation is a capsule, and the capsule includes the solid dispersion described in the first aspect, tragacanth gum and magnesium aluminum silicate.
  • the sustained-release preparation for anti-cervical spondylosis includes the solid dispersion described in the first aspect, other components with anti-cervical spondylosis activity or components with auxiliary anti-cervical spondylosis activity, and pharmaceutically necessary excipients.
  • the other ingredients with auxiliary anti-cervical spondylosis activities include but are not limited to anti-inflammatory drugs, analgesic drugs and trophic neurotrophic drugs.
  • a preparation method of a solid dispersion for the treatment of cervical spondylosis comprises the following steps:
  • step (6) Mix the solid conjugate obtained in step (5), the notoginseng-ethyl cellulose conjugate obtained in step (1), and the volatile oil inclusion product obtained in step (2) through high-speed ball milling to obtain the solid Dispersion; the ball milling speed is 130r/min, and the ball milling time is 1.5h.
  • a preparation method of a solid dispersion for the treatment of cervical spondylosis comprises the following steps:
  • step (6) Mix the solid conjugate obtained in step (5), the notoginseng-ethyl cellulose conjugate obtained in step (1), and the volatile oil inclusion product obtained in step (2) through high-speed ball milling to obtain the solid Dispersion; the ball milling speed is 100r/min, and the ball milling time is 1.5h.
  • a preparation method of a solid dispersion for the treatment of cervical spondylosis comprises the following steps:
  • step (6) Mix the solid conjugate obtained in step (5), the notoginseng-ethyl cellulose conjugate obtained in step (1), and the volatile oil inclusion product obtained in step (2) through high-speed ball milling to obtain the solid Dispersion, the ball milling speed is 100r/min, and the ball milling time is 1.5h.
  • a preparation method of a solid dispersion for the treatment of cervical spondylosis comprises the following steps:
  • step (6) Mix the solid conjugate obtained in step (5), the notoginseng-ethyl cellulose conjugate obtained in step (1), and the volatile oil inclusion complex obtained in step (2) by ball milling to obtain the solid dispersion body; the ball milling speed is 120r/min, and the ball milling time is 1.5h.
  • a sustained-release tablet for the treatment of cervical spondylosis is provided, and the raw material composition and proportioning ratio of the sustained-release tablet are as follows:
  • Preparation method Weigh the solid dispersion described in Example 1 and pulverize it through a 100-mesh sieve, mix the sodium alginate and modified starch in the recipe quantity, and then add them to the sieved solid dispersion in batches. The process of adding Stir continuously to make it completely uniform, finally add the magnesium stearate of the recipe, mix for 10-12 minutes, and press the tablet by a high-speed tableting machine to obtain the sustained-release tablet.
  • a sustained-release tablet for the treatment of cervical spondylosis is provided, and the raw material composition and proportioning ratio of the sustained-release tablet are as follows:
  • Preparation method Weigh the solid dispersion described in Example 1 and pulverize it through a 100-mesh sieve, mix the alginic acid and modified starch in the recipe amount, and then add them to the sieved solid dispersion in batches. Continuously stirring to make it completely mixed, finally adding the prescribed amount of magnesium stearate and then mixing for 13 minutes, and then compressed by a high-speed tableting machine to obtain the sustained-release tablet.
  • a sustained-release tablet for the treatment of cervical spondylosis is provided, and the raw material composition and proportioning ratio of the sustained-release tablet are as follows:
  • Preparation method Weigh the solid dispersion described in Example 1 and pulverize it through a 100-mesh sieve, mix the alginic acid and microcrystalline cellulose of the recipe amount, and then add it to the sieved solid dispersion in batches. The process of adding Stir continuously to make it completely uniform, finally add the prescribed amount of magnesium aluminum silicate and mix for 20 minutes, and press the tablet by a rotary tableting machine to obtain the sustained-release tablet.
  • a slow-release capsule for the treatment of cervical spondylosis is provided, and the raw material composition and proportion of the slow-release capsule are as follows:
  • Preparation method Weigh the solid dispersion described in Example 1 and pulverize it through a 100-mesh sieve, mix the alginic acid and tragacanth in the recipe amount for 20 minutes, and pack 0.5 g of each capsule.
  • a solid dispersion is provided, wherein the solid dispersion is made by mixing Panax notoginseng micropowder with hydroxypropyl cellulose in a mass ratio of 1:0.6, and the rest of the setting methods are the same as those in Embodiment 1.
  • a solid dispersion is provided.
  • the clear paste obtained in step (5) is dried in an oven at 40° C. overnight, pulverized to 200 mesh, and then obtained in step (1).
  • the notoginseng-ethylcellulose combination, the volatile oil inclusions obtained in step (2) are mixed by high-speed ball milling to obtain the solid dispersion.
  • the rest of the steps are set in the same manner as in Example 1.
  • Ginsenoside Rg1, ginsenoside Rb1, and Panax notoginseng saponin R1 which are the landmark components in Jingtong Granules, were selected for in vitro drug release performance investigation.
  • the release degree of the preparation described in Comparative Examples 1-3 was measured, and the release medium was artificial intestinal fluid.
  • 5 parts of the analyte were accurately weighed and placed in the dissolution cup, 5ml was sampled at each time point for measurement, and the cumulative release percentage was calculated at the same time. The results are shown in Figure 1.
  • the ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1 are determined according to the method described in the patent CN104887771A.
  • the three active ingredients in the solid dispersion provided in Example 1, notoginsenoside Rg1, ginsenoside Rg1 and ginsenoside Rb1 all have stable release effects within 12h, wherein the notoginsenoside Rg1 has a stable release effect.
  • the cumulative release amount can reach about 80%, which proves that the above-mentioned active ingredients can achieve sustained and stable release within 12 hours after taking the drug, and the release is relatively complete.
  • the sustained-release preparation in Comparative Example 3 showed a burst release phenomenon in 4-8 hours, indicating that the preparation in Comparative Example 3 may be unstable, resulting in a sudden acceleration of the dissolution rate of Panax notoginseng saponins Rg1.
  • the release amount of the index substance for neck pain product quality detection was also detected, and the detection results are shown in Table 1 below;

Landscapes

  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Mycology (AREA)
  • Biotechnology (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Microbiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Inorganic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Preparation (AREA)

Abstract

Provided are a solid dispersion for treating cervical spondylosis and the use thereof in the preparation of a sustained-release preparation. A cervicodynia product has a good clinical treatment effect as a first-line medicine for treating cervical spondylotic radiculopathy. In order to further reduce the dosage frequency of the cervicodynia product and reduce the medicine usage difficulty of a patient, provided is a sustained-release preparation of the cervicodynia product, and solid dispersion technology is used for the sustained-release preparation. The release performance of the index components Panax notoginseng saponins and ginseng total saponins is effectively achieved, and the release performance of Panax notoginseng saponins is close to first-order kinetics. For the solid dispersion the administration frequency can be reduced, and the solid dispersion can be applied to tablet preparation and is expected to be used as a substitute dosage form of an existing cervicodynia product.

Description

一种治疗颈椎病的固体分散体及在制备缓释制剂中的应用A kind of solid dispersion for treating cervical spondylosis and its application in preparing sustained-release preparation 技术领域technical field
本发明属于中药缓释制剂技术领域，具体涉及一种用于治疗颈椎病的固体分散体及所述固体分散体在制备缓释制剂中的应用。The invention belongs to the technical field of sustained-release preparations of traditional Chinese medicines, and in particular relates to a solid dispersion for treating cervical spondylosis and the application of the solid dispersion in the preparation of sustained-release preparations.
背景技术Background technique
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解，而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。The disclosure of information in this Background section is only for enhancement of understanding of the general background of the invention and should not necessarily be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person of ordinary skill in the art.
颈椎病是一种常见的多发的退行性病患，在50岁左右的人群中有25％的人患病，60岁则达到50％，79岁以后可达到80％～90％。颈椎病的常见类型包括颈型颈椎病、神经根型颈椎病、脊髓型颈椎病、椎动脉型颈椎病、交感神经型颈椎病、食管压迫型颈椎病。其中，神经根损伤是颈椎病中发病率最高的类型，占颈椎病发病的60％。由于该疾病通常以颈椎盘退变为先导，在椎间孔狭窄的基础上，神经根收到机械压迫和化学刺激而产生充血、水肿和炎症而发病，中医将神经根型颈椎病划归为血瘀气滞及脉络闭阻症，属于“痹症”的范畴。Cervical spondylosis is a common multiple degenerative disease. It affects 25% of people around the age of 50, 50% at the age of 60, and 80% to 90% after the age of 79. Common types of cervical spondylosis include cervical spondylosis, radiculopathy, cervical spondylosis myelopathy, vertebral artery cervical spondylosis, sympathetic cervical spondylosis, and esophageal compression cervical spondylosis. Among them, nerve root injury is the type with the highest incidence in cervical spondylosis, accounting for 60% of cervical spondylosis. Because the disease is usually preceded by cervical disc degeneration, and on the basis of intervertebral foramen stenosis, the nerve roots are mechanically compressed and chemically stimulated, resulting in congestion, edema and inflammation. Traditional Chinese medicine classifies cervical radiculopathy as a Blood stasis and qi stagnation and choroidal obstructive disease belong to the category of "arthritis".
颈痛颗粒是一种用于神经根型颈椎病的口服中药复方制剂，具有活血化瘀，行气止痛的功效，在临床治疗中具有令人满意的疗效。所述中药复方包括三七、川芍、延胡索、葛根、威灵仙、羌活。方中：三七、川芍为君药，活血化痊，行气止痛，且三七活血化疲为骨伤要药，文献记载，三七能化骨髓之疲血，防骨中髓外出，痊阻自通，痹痛自除。所谓通则不痛，通则筋脉得养，气血以和，麻木缓解；延胡索、威灵仙、羌活能增强三七、川芍的活血行气之功，兼祛风寒湿邪外出，是为臣药；白芍为佐药，养血敛阴，濡养筋脉，缓急止痛，缓解 麻木、疼痛之症亦可防温燥太过伤阴；葛根能解除肌肉痉挛，引诸药达病所而为使药，诸药合用，能达活血化疲，行气止痛之效。Jingtong Granule is an oral traditional Chinese medicine compound preparation for radiculopathy of cervical spondylosis. The traditional Chinese medicine compound includes Panax notoginseng, Sichuan peony root, Corydalis japonica, Pueraria lobata, Weilingxian, and Qianghuo. In the prescription: Panax notoginseng and Chuan peony are the monarch medicines, which can promote blood circulation and improve recovery, promote qi and relieve pain, and Panax notoginseng is an essential medicine for bone injuries. According to the literature, Panax notoginseng can transform the fatigue and blood of the bone marrow, and prevent the marrow from going out of the bone. Recovered from obstruction and self-opening, arthralgia self-eliminated. The so-called general rule does not have pain, general rule is the nourishment of tendons and meridians, qi and blood are harmonious, and numbness is relieved. Medicine; Paeonia lactiflora is an adjuvant, nourishing blood and astringing yin, moisturizing and nourishing tendons and meridians, relieving acute pain, relieving numbness and pain, and preventing excessive heat and dryness from hurting yin; Pueraria lobata can relieve muscle spasm and induce various medicines to reach the place of disease. In order to make the medicine, the combination of various medicines can achieve the effect of promoting blood circulation and eliminating fatigue, activating qi and relieving pain.
目前在售的颈痛系列产品包括颈痛颗粒、颈痛胶囊及颈痛片，由于颗粒剂服用时口苦味重，胶囊及片剂能够有效的克服该缺陷。但是，为了保证有效药物剂量，特别是有效缓解重症患者持续不止的疼痛症状，片剂和胶囊剂的服用剂量较大，颈痛片每次4片，每日三次服用，颈痛胶囊则需要一次五粒，一日三次服用。针对该现状，提供所述颈通产品的缓释制剂能够有效的降低给药次数。多组分是中药制剂的重要组成特点，为了发挥药物整体疗效，实现药物中多组分的同步释放具有重要的意义。目前，口服中药多组分同步释放技术主要包括多层压片技术、多元定位释药技术、多元定时技术、渗透泵技术、固体分散技术等。从剂型角度可分为骨架型缓释制剂、膜控型缓释制剂以及渗透泵型缓释制，其中，骨架缓释制剂作为一种常见的缓释剂型，主要应用多层压片或固体分散技术，制备工艺简单，易于工业化生产。Neck pain products currently on sale include Neck Pain Granules, Neck Pain Capsules and Neck Pain Tablets. Since the granules have a heavy taste when taken, capsules and tablets can effectively overcome this defect. However, in order to ensure the effective dose of drugs, especially to effectively relieve the persistent pain symptoms of severe patients, the dosage of tablets and capsules is relatively large. Neck Pain Tablets are 4 tablets each time, three times a day, while Neck Pain Capsules need to be taken once a day. Five capsules, three times a day. In view of this situation, providing the sustained-release preparation of the neck passage product can effectively reduce the number of administrations. Multi-component is an important characteristic of traditional Chinese medicine preparations. In order to exert the overall efficacy of the drug, it is of great significance to realize the simultaneous release of multiple components in the drug. At present, the multi-component synchronous release technology of oral traditional Chinese medicine mainly includes multi-layer tablet technology, multi-positioned drug release technology, multi-timed technology, osmotic pump technology, solid dispersion technology, etc. From the perspective of dosage form, it can be divided into matrix-type sustained-release preparations, membrane-controlled sustained-release preparations and osmotic pump-type sustained-release preparations. Among them, matrix sustained-release preparations are a common sustained-release dosage form. technology, the preparation process is simple, and the industrial production is easy.
发明内容SUMMARY OF THE INVENTION
针对上述背景技术中记载的现状，本发明目的在于提供一种颈痛产品的缓释制剂，通过对现有颈痛系列产品制备工艺和辅料的优化，提供一种能够缓慢、持续并且长效释放的剂型，减少患者用药次数。In view of the current situation recorded in the above-mentioned background art, the object of the present invention is to provide a slow-release preparation for a neck pain product, by optimizing the preparation process and auxiliary materials of the existing neck pain series products, to provide a slow, sustained and long-acting release preparation dosage form, reducing the number of patients taking medication.
基于上述技术目的，本发明提供以下技术方案：Based on the above-mentioned technical purpose, the present invention provides the following technical solutions:
本发明第一方面，提供一种用于颈椎病的固体分散体，所述固体分散体制备方法如下：将三七粉与乙基纤维素混合得到三七-乙基纤维素结合物；In a first aspect of the present invention, a solid dispersion for cervical spondylosis is provided, and the preparation method of the solid dispersion is as follows: mixing Panax notoginseng powder and ethyl cellulose to obtain a notoginseng-ethyl cellulose combination;
所述羌活、威灵仙提取其中的挥发油与倍他环糊精得到包合物，剩余的药材煎煮过滤得到滤液；The volatile oil and beta cyclodextrin are extracted from the Qiang Huo and Wei Lingxian to obtain an inclusion compound, and the remaining medicinal materials are decocted and filtered to obtain a filtrate;
葛根、白芍加水煎煮后浓缩，加入乙醇搅拌过滤得到滤液部分，将所述羌 活、威灵仙滤液及葛根、白芍滤液以及川芎、延胡索的醇提液混合得到一种混合滤液，去除所述混合滤液的溶剂得到清膏，将所述清膏与氧化镁混合粉碎得到固体结合物；Pueraria lobata and Radix Paeoniae Alba are boiled with water and concentrated, add ethanol, stir and filter to obtain a filtrate part, mix the ethanol extracts of the Radix Radix et Rhizoma, Wei Lingxian filtrate, Pueraria Root, Radix Paeoniae Alba filtrate, Chuanxiong Radix, and Corydalis Rhizoma to obtain a mixed filtrate, remove all the filtrate. The solvent of the mixed filtrate obtains a clear paste, and the clear paste and magnesium oxide are mixed and pulverized to obtain a solid combination;
将所述三七-乙基纤维素结合物、包合物及固体结合物混合均匀得到所述固体分散体。The solid dispersion is obtained by uniformly mixing the notoginseng-ethylcellulose combination, the inclusion compound and the solid combination.
根据本领域的一般研究思路，三七作为贵重药材，通常采用粉碎后直接入药的方式保留全部药用部位。三七中的主要活性成分三七总皂苷对于发挥活血化瘀的功效也具有重要意义。针对缓释制剂中三七的处理方式，本发明首先通过将其粉碎成为细粉或超细粉，增加三七总皂苷的溶出总量，另外采用乙基纤维素作为辅助分散剂，乙基纤维素在酸性条件下也具有良好的稳定性，做为口服制剂缓释剂，能够很好的实现三七总皂苷的持续释放效果，几乎接近一级动力学释放效果。另外，本发明研究还发现，采用乙基纤维素与氧化镁的配合，该固体分散体中挥发油、清膏及三七总皂苷类成分均可以实现基本同步的释放效果，所述颈通产品中的指标性成分三七总皂苷及人参总皂苷均能实现良好的长效、缓释效果，提高生物利用度。According to the general research ideas in this field, Panax notoginseng, as a valuable medicinal material, is usually crushed and directly used as medicine to retain all the medicinal parts. The main active ingredient in Panax notoginseng, the total saponins of Panax notoginseng, is also of great significance for exerting the effect of promoting blood circulation and removing blood stasis. Regarding the treatment method of Panax notoginseng in the sustained-release preparation, the present invention firstly pulverizes it into fine powder or ultrafine powder to increase the total amount of total saponins dissolved in Panax notoginseng. In addition, ethyl cellulose is used as an auxiliary dispersant, ethyl cellulose It also has good stability under acidic conditions. As a sustained release agent for oral preparations, it can well achieve the sustained release effect of total saponins from Panax notoginseng, which is almost close to the first-order kinetic release effect. In addition, the research of the present invention also found that by using the combination of ethyl cellulose and magnesium oxide, the volatile oil, clear paste and Panax notoginseng saponins in the solid dispersion can achieve a basically synchronous release effect. The index components of Panax notoginseng saponins and ginseng total saponins can achieve good long-acting and slow-release effects and improve bioavailability.
本发明第二方面，提供第一方面所述治疗颈椎病的固体分散体在制备抗颈椎病缓释制剂中的应用。The second aspect of the present invention provides the application of the solid dispersion for treating cervical spondylosis described in the first aspect in the preparation of an anti-cervical spondylosis sustained-release preparation.
以上一个或多个技术方案的有益效果是：The beneficial effects of the above one or more technical solutions are:
本发明提供的固体分散体，通过对现有颈痛颗粒制备工艺进行了简单的改进，实现了指标性成分的良好缓释效果，其释放效果接近一级动力学释放效果，释放时间可达12h，总释放量也显著优于现有药物。The solid dispersion provided by the present invention achieves a good slow-release effect of the index components by simply improving the preparation process of the existing neck pain granules, the release effect is close to the first-order kinetic release effect, and the release time can reach 12h , the total release is also significantly better than existing drugs.
另外，该固体分散体制剂具有良好的稳定性和加工性能，应用于片剂、胶囊剂及其他固体剂型的制备具有良好的开发潜力，有望为现有颈痛系列产品的 替代产品。In addition, the solid dispersion preparation has good stability and processing performance, and has good development potential when applied to the preparation of tablets, capsules and other solid dosage forms, and is expected to be a substitute product for the existing neck pain series products.
附图说明Description of drawings
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。The accompanying drawings forming a part of the present invention are used to provide further understanding of the present invention, and the exemplary embodiments of the present invention and their descriptions are used to explain the present invention, and do not constitute an improper limitation of the present invention.
图1为实施例9中体外释药性能曲线图；Fig. 1 is a graph of in vitro drug release performance in Example 9;
其中，图1A为实施例1及对比例1-3所述制剂中三七皂苷Rg1体外释放曲线图；Wherein, Fig. 1A is a graph showing the in vitro release curve of notoginsenoside Rg1 in the preparations described in Example 1 and Comparative Examples 1-3;
图1B为实施例1-4所述制剂中三七皂苷Rg1体外释放曲线图；Figure 1B is a graph showing the in vitro release curve of notoginsenoside Rg1 in the preparations described in Examples 1-4;
图1C为实施例1中所述固体分散体中三种指标性成分的体外释放曲线图。FIG. 1C is a graph showing the in vitro release profiles of the three indicator components in the solid dispersion described in Example 1. FIG.
具体实施方式detailed description
应该指出，以下详细说明都是例示性的，旨在对本发明提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。It should be noted that the following detailed description is exemplary and intended to provide further explanation of the invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
需要注意的是，这里所使用的术语仅是为了描述具体实施方式，而非意图限制根据本发明的示例性实施方式。如在这里所使用的，除非上下文另外明确指出，否则单数形式也意图包括复数形式，此外，还应当理解的是，当在本说明书中使用术语“包含”和/或“包括”时，其指明存在特征、步骤、操作、器件、组件和/或它们的组合。It should be noted that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to limit the exemplary embodiments according to the present invention. As used herein, unless the context clearly dictates otherwise, the singular is intended to include the plural as well, furthermore, it is to be understood that when the terms "comprising" and/or "including" are used in this specification, it indicates that There are features, steps, operations, devices, components and/or combinations thereof.
正如背景技术所介绍的，针对现有颈痛颗粒服药次数多的弊端，为了解决如上的技术问题，本发明提出了一种用于治疗颈椎病的缓释制剂。As described in the background art, in order to solve the above-mentioned technical problem, the present invention proposes a sustained-release preparation for treating cervical spondylosis in view of the drawbacks of the existing neck pain granules that are taken frequently.
本发明第一方面，提供一种治疗颈椎病的固体分散体，所述固体分散体制备方法如下：将三七粉与乙基纤维素混合得到三七-乙基纤维素结合物；The first aspect of the present invention provides a solid dispersion for treating cervical spondylosis, and the preparation method of the solid dispersion is as follows: mixing Panax notoginseng powder and ethyl cellulose to obtain a notoginseng-ethyl cellulose combination;
所述羌活、威灵仙提取其中的挥发油与倍他环糊精得到包合物，剩余的药 材煎煮过滤得到滤液；Described Qianghuo, Wei Lingxian extract wherein the volatile oil and beta cyclodextrin obtain inclusion compound, and the remaining medicinal materials are decocted and filtered to obtain filtrate;
葛根、白芍加水煎煮后浓缩，加入乙醇搅拌过滤得到滤液部分，将所述羌活、威灵仙滤液及葛根、白芍滤液以及川芎、延胡索的醇提液混合得到一种混合滤液，去除所述混合滤液的溶剂得到清膏，将所述清膏与氧化镁混合粉碎得到固体结合物；Pueraria lobata and Radix Paeoniae Alba are boiled with water and concentrated, add ethanol, stir and filter to obtain a filtrate part, mix the ethanol extracts of the Radix Radix et Rhizoma, Wei Lingxian filtrate, Pueraria Root, Radix Paeoniae Alba filtrate, Chuanxiong Radix, and Corydalis Rhizoma to obtain a mixed filtrate, remove all the filtrate. The solvent of the mixed filtrate obtains a clear paste, and the clear paste and magnesium oxide are mixed and pulverized to obtain a solid combination;
将所述三七-乙基纤维素结合物、包合物及固体结合物混合均匀得到所述固体分散体。The solid dispersion is obtained by uniformly mixing the notoginseng-ethylcellulose combination, the inclusion compound and the solid combination.
优选的，所述三七、羌活、威灵仙、葛根、白芍、川芎及延胡索的质量比为35～38：100：100：95：95：80～85：60～65。Preferably, the mass ratio of the Panax notoginseng, Qianghuo, Weilingxian, Puerariae, Baishao, Chuanxiong and Corydalis is 35-38:100:100:95:95:80-85:60-65.
优选的，所述三七粉为微粉或超微粉，目数为200目及以上。Preferably, the Panax notoginseng powder is micro powder or superfine powder, and the mesh number is 200 mesh and above.
优选的，所述三七粉与乙基纤维素的加入比例为1:0.5～0.7。Preferably, the addition ratio of the Panax notoginseng powder to ethyl cellulose is 1:0.5-0.7.
根据本领域的一般研究思路，三七作为贵重药材，通常采用粉碎后直接入药的方式保留全部药用部位。三七中的主要活性成分三七总皂苷对于发挥活血化瘀的功效也具有重要意义。针对缓释制剂中三七的处理方式，本发明首先通过将其粉碎成为细粉或超细粉，增加三七总皂苷的溶出效果，另外采用乙基纤维素作为辅助分散剂，羟丙基甲纤维素在酸性条件下也具有良好的稳定性，并且具有凝胶性，能够很好的实现三七总皂苷的持续释放效果，几乎接近一级动力学释放效果。另外，本发明研究还发现，采用乙基纤维素与氧化镁的配合作用下，该固体分散体中挥发油、清膏及三七总皂苷类成分均可以实现基本同步的释放效果。According to the general research ideas in this field, Panax notoginseng, as a valuable medicinal material, is usually crushed and directly used as medicine to retain all the medicinal parts. The main active ingredient in Panax notoginseng, the total saponins of Panax notoginseng, is also of great significance for exerting the effect of promoting blood circulation and removing blood stasis. Regarding the treatment method of Panax notoginseng in the sustained-release preparation, the present invention firstly pulverizes it into fine powder or ultrafine powder to increase the dissolution effect of the total saponins of Panax notoginseng. Cellulose also has good stability under acidic conditions and has gel properties, which can well achieve the sustained release effect of Panax notoginseng total saponins, which is almost close to the first-order kinetic release effect. In addition, the research of the present invention also finds that under the cooperative action of ethyl cellulose and magnesium oxide, the volatile oil, clear paste and Panax notoginseng saponins in the solid dispersion can achieve a basically synchronous release effect.
优选的，所述三七与乙基纤维素通过球磨混合；进一步优选的，所述球磨混合的速率为80～120r/min，时间为0.4～0.5h。Preferably, the notoginseng and ethyl cellulose are mixed by ball milling; further preferably, the mixing speed of the ball milling is 80-120 r/min, and the time is 0.4-0.5 h.
优选的，所述挥发油采用倍他环糊精包合在蒸汽及搅拌作用下进行包合。Preferably, the volatile oil is packaged by betacyclodextrin under the action of steam and stirring.
在所述优选技术方案的一些具体实施方式中，所述包合物制备方法采用专利CN104887771A中[0010]段记载的方法进行包合，包合率稳定达到85～90％。In some specific embodiments of the preferred technical solution, the inclusion compound preparation method adopts the method described in paragraph [0010] of patent CN104887771A for inclusion, and the inclusion rate is stable at 85-90%.
优选的，所述羌活、威灵仙提取挥发油之后的药材加水煎煮2～4次，并将数次的煎煮液合并过滤得到所述滤液。Preferably, the medicinal materials obtained from the extraction of volatile oil from Qianghuo and Weilingxian are decocted with water for 2 to 4 times, and the decoctions of several times are combined and filtered to obtain the filtrate.
优选的，所述葛根、白芍加水煎煮后浓缩，加入乙醇搅拌过滤得到滤液部分具体步骤如下：将葛根、白芍加水煎煮2～4次，将数次煎煮液合并并过滤得到滤液，将所述滤液浓缩至密度为1.10～1.15，向浓缩后的滤液中加入乙醇至溶液中乙醇浓度达到60～70％，搅拌后过滤得到滤液部分。Preferably, the pueraria root and Radix Paeoniae Alba are boiled in water and then concentrated, and then added with ethanol to stir and filter to obtain the filtrate. The specific steps are as follows: decocting the Radix Puerariae and the Radix Paeoniae Alba in water for 2 to 4 times, and combining and filtering the decocted liquids for several times to obtain the filtrate , the filtrate is concentrated to a density of 1.10-1.15, ethanol is added to the concentrated filtrate until the ethanol concentration in the solution reaches 60-70%, and the filtrate is obtained by filtration after stirring.
优选的，所述川芎、延胡索的醇提液制备方法如下：向川芎、延胡索中加入乙醇回流提取2～4次，合并数次回流的提取液，过滤得到滤液。Preferably, the preparation method of the alcohol extract of Chuanxiong and Corydalis is as follows: adding ethanol to Chuanxiong and Corydalis for 2 to 4 times of reflux extraction, merging the refluxed extracts for several times, and filtering to obtain a filtrate.
优选的，所述所述羌活、威灵仙滤液及葛根、白芍滤液以及川芎、延胡索的醇提液混合后在水浴条件下加热搅拌一段时间得到所述混合溶液。Preferably, the mixed solution is obtained by mixing the Qianghuo, Weilingxian filtrate, Pueraria lobata filtrate, and the alcohol extracts of Chuanxiong and Corydalis Fructus, and heating and stirring for a period of time under water bath conditions.
进一步优选的，所述水浴温度为45～50℃。Further preferably, the temperature of the water bath is 45-50°C.
进一步优选的，所述水浴时间为3～3.5h。Further preferably, the water bath time is 3-3.5h.
优选的，所述混合滤液通过减压蒸馏除去部分溶剂及溶剂中的乙醇，干燥得到所述清膏。Preferably, the mixed filtrate is distilled under reduced pressure to remove part of the solvent and ethanol in the solvent, and then dried to obtain the clear paste.
进一步优选的，所述减压蒸馏的真空度为-0.03～-0.07M Pa。Further preferably, the vacuum degree of the vacuum distillation is -0.03～-0.07MPa.
进一步优选的，所述干燥的方式包括但不限于采用喷雾干燥、真空干燥或冷冻干燥。Further preferably, the drying method includes, but is not limited to, spray drying, vacuum drying or freeze drying.
优选的，所述去除溶剂后得到清膏之后还包括对清膏进行干燥处理的步骤，所述干燥在40～45℃烘干处理。Preferably, after removing the solvent to obtain the clear paste, it further includes a step of drying the clear paste, and the drying is performed at 40-45°C.
优选的，所述清膏与氧化镁的质量比为1:0.01～0.02。Preferably, the mass ratio of the clear paste to magnesium oxide is 1:0.01-0.02.
优选的，所述清膏与氧化镁的混合方式如下：将称量好的氧化镁分批次加 入清膏中通过粉碎机进行粉碎。Preferably, the mixing mode of the clear paste and magnesium oxide is as follows: the weighed magnesium oxide is added to the clear paste in batches and pulverized by a pulverizer.
优选的，所述固体结合物、三七-乙基纤维素结合物及挥发油包合物通过球磨混合均匀。Preferably, the solid conjugate, the notoginseng-ethyl cellulose conjugate and the volatile oil inclusion complex are uniformly mixed by ball milling.
进一步优选的，所述球磨转速为100～130r/min，时间为1～1.5h。Further preferably, the rotation speed of the ball mill is 100-130r/min, and the time is 1-1.5h.
本发明第二方面，提供第一方面所述治疗颈椎病的固体分散体在制备抗颈椎病缓释制剂中的应用。The second aspect of the present invention provides the application of the solid dispersion for treating cervical spondylosis described in the first aspect in the preparation of an anti-cervical spondylosis sustained-release preparation.
优选的，所述抗颈椎病缓释制剂为口服剂型，所述口服剂型包括但不限于颗粒剂、片剂、胶囊剂、散剂、丸剂等。Preferably, the anti-cervical spondylosis sustained-release preparation is an oral dosage form, and the oral dosage form includes, but is not limited to, granules, tablets, capsules, powders, pills, and the like.
优选的，所述抗颈椎病缓释制剂中包括第一方面所述固体分散体及药学上所必须的辅料。Preferably, the anti-cervical spondylosis sustained-release preparation includes the solid dispersion described in the first aspect and pharmaceutically necessary excipients.
进一步优选的，所述抗颈椎病缓释制剂为片剂，所述片剂中包括第一方面所述固体分散体，还包括粘合剂及润滑剂。Further preferably, the anti-cervical spondylosis sustained-release preparation is a tablet, and the tablet includes the solid dispersion described in the first aspect, and also includes a binder and a lubricant.
更进一步的，所述润滑剂为包括但不限于改性淀粉、硬质酸钠、硅铝酸镁中的一种或几种的混合。Further, the lubricant includes, but is not limited to, one or a mixture of modified starch, sodium stearate, and magnesium aluminosilicate.
更进一步的，所述粘合剂为包括但不限于西黄蓍胶、壳聚糖、海藻酸、海藻酸钠中的一种或几种的组合。Further, the adhesive includes but not limited to one or a combination of tragacanth, chitosan, alginic acid, and sodium alginate.
在上述优选技术方案的一些具体实施方式中，所述片剂中包括第一方面所述固体分散体、改性淀粉及硬脂酸镁。In some specific embodiments of the above preferred technical solutions, the tablet includes the solid dispersion described in the first aspect, modified starch and magnesium stearate.
在上述优选技术方案的一些具体实施方式中，所述片剂中包括第一方面所述固体分散体、海藻酸、改性淀粉及硬脂酸镁。In some specific embodiments of the above preferred technical solutions, the tablet includes the solid dispersion described in the first aspect, alginic acid, modified starch and magnesium stearate.
在上述优选技术方案的一些具体实施方式中，所述片剂中包括第一方面所述固体分散体、海藻酸、微晶纤维素及硅酸镁铝。In some specific embodiments of the above preferred technical solutions, the tablet includes the solid dispersion of the first aspect, alginic acid, microcrystalline cellulose and magnesium aluminum silicate.
更进一步的，所述抗颈椎病缓释制剂为胶囊剂，所述胶囊剂包括第一方面 所述固体分散体、西黄蓍胶及硅酸镁铝。Further, the anti-cervical spondylosis sustained-release preparation is a capsule, and the capsule includes the solid dispersion described in the first aspect, tragacanth gum and magnesium aluminum silicate.
优选的，所述抗颈椎病缓释制剂中包括第一方面所述固体分散体、其他具有抗颈椎病活性的成分或辅助抗颈椎病活性的成分，及药学上所必须的辅料。Preferably, the sustained-release preparation for anti-cervical spondylosis includes the solid dispersion described in the first aspect, other components with anti-cervical spondylosis activity or components with auxiliary anti-cervical spondylosis activity, and pharmaceutically necessary excipients.
进一步优选的，所述其他具有辅助抗颈椎病活性的成分包括但不限于抗炎药物、镇痛药物及营养神经型药物。Further preferably, the other ingredients with auxiliary anti-cervical spondylosis activities include but are not limited to anti-inflammatory drugs, analgesic drugs and trophic neurotrophic drugs.
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案，以下将结合具体的实施例与对比例详细说明本发明的技术方案。In order to enable those skilled in the art to understand the technical solutions of the present invention more clearly, the technical solutions of the present invention will be described in detail below with reference to specific embodiments and comparative examples.
实施例1Example 1
本实施例中，提供一种用于治疗颈椎病固体分散体的制备方法，所述制备方法包括以下步骤：In the present embodiment, a preparation method of a solid dispersion for the treatment of cervical spondylosis is provided, and the preparation method comprises the following steps:
(1)将三七350g粉碎成微粉，向三七粉末中加入乙基纤维素进行球磨得到一种三七-乙基纤维素结合物，所述三七粉末与乙基纤维素的质量比为1:0.6；所述球磨速度为100r/min，时间为0.5h；(1) pulverize 350 g of Panax notoginseng into micropowder, add ethyl cellulose to the notoginseng powder and perform ball milling to obtain a notoginseng-ethyl cellulose combination, the mass ratio of the notoginseng powder and ethyl cellulose is 1:0.6; the ball milling speed is 100r/min, and the time is 0.5h;
(2)羌活1000g、威灵仙1000g提取挥发油，挥发油用倍他环糊精(1ml：2.1g)包结成包合物，提取挥发油之后的药材加水煎煮煎液滤过；药渣再加水煎煮1小时，滤过，合并二次滤液，备用；(2) Extract volatile oil from 1000g of Qianghuo and 1000g of Weilingxian, and encapsulate the volatile oil with betacyclodextrin (1ml: 2.1g) to form an inclusion complex, add water to decoct the medicinal materials after extracting the volatile oil and filter; add water to the medicinal residues Decoct for 1 hour, filter, combine the secondary filtrate, set aside;
(3)葛根950g、白芍950g加水煎煮二次，第一次1.5小时，第二次1小时，合并煎液，滤过，滤液与上述滤液合并，浓缩至相对密度为1.12(50℃)，加乙醇使含醇量达60％，搅匀，冷藏过夜，滤过，滤渣用60％乙醇洗涤一次，洗涤液滤过，与上述滤液合并，得到所述葛根、白芍滤液；(3) 950g of Radix Puerariae and 950g of Paeonia lactiflora were added and boiled twice, the first time was 1.5 hours, the second time was 1 hour, the decoction was combined, filtered, and the filtrate was combined with the above-mentioned filtrate, and concentrated to a relative density of 1.12 (50° C.) , add ethanol to make the alcohol content reach 60%, stir evenly, refrigerate overnight, filter, the filter residue is washed once with 60% ethanol, the washing solution is filtered, and combined with the above-mentioned filtrate to obtain the Pueraria lobata and Radix Paeoniae Alba filtrate;
(4)川芎800g、延胡索600g加乙醇加热回流提取二次，第一次2小时，第二次1小时，合并提取液，静置过夜，滤过，与步骤(2)、(3)中得到的滤液合并，得到一种混合滤液；(4) 800g of Chuanxiong, 600g of Corydalis Radix are added with ethanol heating and refluxing to extract twice, the first time is 2 hours, the second time is 1 hour, the extracts were combined, left standing overnight, filtered, and obtained in steps (2) and (3) The filtrates were combined to obtain a mixed filtrate;
(5)将上述混合滤液在50℃水浴条件下加热搅拌3h，过滤后将滤液在真空度-0.03～-0.07M Pa条件下旋蒸除去部分乙醇，之后在喷雾干燥方式下去除溶剂得到清膏，将清膏置于烘箱中40℃干燥过夜后粉碎至200目，粉碎过程中按照质量比1:0.01分多次加入氧化镁，得到一种固体结合物；(5) The above mixed filtrate was heated and stirred for 3h under the condition of a 50°C water bath, after filtration, the filtrate was rotary evaporated under the condition of vacuum degree -0.03～-0.07MPa to remove part of the ethanol, and then the solvent was removed under the spray drying method to obtain a clear paste , the clear paste is placed in an oven at 40 °C to dry overnight and then pulverized to 200 mesh. During the pulverization process, magnesium oxide is added multiple times according to the mass ratio of 1:0.01 to obtain a solid combination;
(6)将步骤(5)得到的固体结合物、步骤(1)得到的三七-乙基纤维素结合物，步骤(2)得到的挥发油包结物混合通过高速球磨混均得到所述固体分散体；所述球磨转速为130r/min，球磨时间为1.5h。(6) Mix the solid conjugate obtained in step (5), the notoginseng-ethyl cellulose conjugate obtained in step (1), and the volatile oil inclusion product obtained in step (2) through high-speed ball milling to obtain the solid Dispersion; the ball milling speed is 130r/min, and the ball milling time is 1.5h.
实施例2Example 2
本实施例中，提供一种用于治疗颈椎病固体分散体的制备方法，所述制备方法包括以下步骤：In the present embodiment, a preparation method of a solid dispersion for the treatment of cervical spondylosis is provided, and the preparation method comprises the following steps:
(1)将三七350g粉碎成微粉，向三七粉末中加入乙基纤维素进行球磨得到一种三七-乙基纤维素结合物，所述三七粉末与乙基纤维素的质量比为1:0.5，所述球磨速度为80r/min，时间为0.5h；(1) pulverize 350 g of Panax notoginseng into micropowder, add ethyl cellulose to the notoginseng powder and perform ball milling to obtain a notoginseng-ethyl cellulose combination, the mass ratio of the notoginseng powder and ethyl cellulose is 1:0.5, the ball milling speed is 80r/min, and the time is 0.5h;
(2)羌活1000g、威灵仙1000g提取挥发油，挥发油用倍他环糊精(1ml：2.0g)包结成包合物，提取挥发油之后的药材加水煎煮煎液滤过；药渣再加水煎煮1小时，滤过，合并二次滤液，备用；(2) Extract volatile oil from 1000g of Qianghuo and 1000g of Weilingxian, and encapsulate the volatile oil with betacyclodextrin (1ml: 2.0g) to form an inclusion complex, add water to decoct the medicinal material after extracting the volatile oil and filter it; add water to the medicinal residues Decoct for 1 hour, filter, combine the secondary filtrate, set aside;
(3)葛根950g、白芍950g加水煎煮二次，第一次1.5小时，第二次1小时，合并煎液，滤过，滤液与上述滤液合并，浓缩至相对密度为1.12(50℃)，加乙醇使含醇量达70％，搅匀，冷藏过夜，滤过，滤渣用70％乙醇洗涤一次，洗涤液滤过，与上述滤液合并，得到所述葛根、白芍滤液；(3) 950g of Radix Puerariae and 950g of Paeonia lactiflora were added and boiled twice, the first time was 1.5 hours, the second time was 1 hour, the decoction was combined, filtered, and the filtrate was combined with the above-mentioned filtrate, and concentrated to a relative density of 1.12 (50° C.) , add ethanol to make the alcohol content reach 70%, stir evenly, refrigerate overnight, filter, the filter residue is washed once with 70% ethanol, the washing solution is filtered, and combined with the above-mentioned filtrate to obtain the Pueraria lobata and Radix Paeoniae Alba filtrate;
(4)川芎800g、延胡索650g加乙醇加热回流提取二次，第一次2小时，第二次1.5小时，合并提取液，静置过夜，滤过，与步骤(2)、(3)中得到的滤液合并，得到一种混合滤液；(4) 800g of Chuanxiong, 650g of Corydalis Radix are added with ethanol heating and refluxing to extract twice, the first time is 2 hours, the second time is 1.5 hours, the extracts were combined, left standing overnight, filtered, and obtained in steps (2) and (3) The filtrates were combined to obtain a mixed filtrate;
(5)将上述混合滤液在50℃水浴条件下加热搅拌3.5h，滤过，将滤液在真空度-0.03～-0.07M Pa条件下旋蒸除去部分乙醇，之后在冷冻干燥方式下去除溶剂得到清膏，将清膏置于烘箱中40℃干燥过夜后粉碎至200目，粉碎过程中按照质量比1:0.02分多次加入氧化镁，得到一种固体结合物；(5) The above mixed filtrate was heated and stirred for 3.5h under the condition of a 50°C water bath, filtered, and the filtrate was rotary-evaporated under the condition of vacuum degree -0.03～-0.07MPa to remove part of the ethanol, and then the solvent was removed under freeze-drying mode to obtain To clear the paste, place the clear paste in an oven at 40°C to dry overnight and then pulverize it to 200 mesh. During the pulverization process, magnesium oxide is added multiple times according to a mass ratio of 1:0.02 to obtain a solid combination;
(6)将步骤(5)得到的固体结合物、步骤(1)得到的三七-乙基纤维素结合物，步骤(2)得到的挥发油包结物混合通过高速球磨混均得到所述固体分散体；所述球磨转速为100r/min，球磨时间为1.5h。(6) Mix the solid conjugate obtained in step (5), the notoginseng-ethyl cellulose conjugate obtained in step (1), and the volatile oil inclusion product obtained in step (2) through high-speed ball milling to obtain the solid Dispersion; the ball milling speed is 100r/min, and the ball milling time is 1.5h.
实施例3Example 3
本实施例中，提供一种用于治疗颈椎病固体分散体的制备方法，所述制备方法包括以下步骤：In the present embodiment, a preparation method of a solid dispersion for the treatment of cervical spondylosis is provided, and the preparation method comprises the following steps:
(1)将三七350g粉碎成微粉，向三七粉末中加入乙基纤维素进行球磨得到一种三七-乙基纤维素结合物，所述三七粉末与乙基纤维素的质量比为1:0.7，所述球磨速度为120r/min，时间为0.4h；(1) pulverize 350 g of Panax notoginseng into micropowder, add ethyl cellulose to the notoginseng powder and perform ball milling to obtain a notoginseng-ethyl cellulose combination, the mass ratio of the notoginseng powder and ethyl cellulose is 1:0.7, the ball milling speed is 120r/min, and the time is 0.4h;
(2)羌活1000g、威灵仙1000g提取挥发油，挥发油用倍他环糊精(1ml：2.2g)包结成包合物，提取挥发油之后的药材加水煎煮煎液滤过；药渣再加水煎煮1.5小时，滤过，合并二次滤液，备用；(2) Extract volatile oil from 1000g of Qianghuo and 1000g of Weilingxian, and encapsulate the volatile oil with betacyclodextrin (1ml: 2.2g) to form an inclusion complex, add water to decoct the medicinal material after extracting the volatile oil and filter it; add water to the medicinal residues Decoct for 1.5 hours, filter, combine the secondary filtrate, set aside;
(3)葛根950g、白芍950g加水煎煮二次，第一次1.5小时，第二次1小时，合并煎液，滤过，滤液与上述滤液合并，浓缩至相对密度为1.12(50℃)，加乙醇使含醇量达60％，搅匀，冷藏过夜，滤过，滤渣用60％乙醇洗涤一次，洗涤液滤过，与上述滤液合并，得到所述葛根、白芍滤液；(3) 950g of Radix Puerariae and 950g of Paeonia lactiflora were added and boiled twice, the first time was 1.5 hours, the second time was 1 hour, the decoction was combined, filtered, and the filtrate was combined with the above-mentioned filtrate, and concentrated to a relative density of 1.12 (50° C.) , add ethanol to make the alcohol content reach 60%, stir evenly, refrigerate overnight, filter, the filter residue is washed once with 60% ethanol, the washing solution is filtered, and combined with the above-mentioned filtrate to obtain the Pueraria lobata and Radix Paeoniae Alba filtrate;
(4)川芎850g、延胡索600g加乙醇加热回流提取二次，第一次2小时，第二次1小时，合并提取液，静置过夜，滤过，与步骤(2)、(3)中得到的滤液合并，得到一种混合滤液；(4) 850g of Chuanxiong, 600g of Corydalis Radix are added with ethanol and heated to reflux for extraction twice, the first time is 2 hours, the second time is 1 hour, the extracts were combined, left standing overnight, filtered, and obtained in steps (2) and (3) The filtrates were combined to obtain a mixed filtrate;
(5)将上述混合滤液在45℃水浴条件下加热搅拌3.5h后过滤，将滤液在真空度-0.03～-0.07M Pa条件下旋蒸除去部分乙醇，之后在真空干燥方式下去除溶剂得到清膏，将清膏置于烘箱中40℃干燥过夜后粉碎至180目，粉碎过程中按照质量比1:0.02分多次加入氧化镁，得到一种固体结合物；(5) The above mixed filtrate was heated and stirred for 3.5h under a water bath at 45°C and filtered, and the filtrate was rotated to remove part of ethanol under the condition of vacuum degree of -0.03～-0.07MPa, and then the solvent was removed under vacuum drying to obtain a clear Place the clear paste in an oven at 40°C to dry overnight and then pulverize it to 180 mesh. During the pulverization process, magnesium oxide is added multiple times according to a mass ratio of 1:0.02 to obtain a solid combination;
(6)将步骤(5)得到的固体结合物、步骤(1)得到的三七-乙基纤维素结合物，步骤(2)得到的挥发油包结物混合通过高速球磨混均得到所述固体分散体，所述球磨转速为100r/min，球磨时间为1.5h。(6) Mix the solid conjugate obtained in step (5), the notoginseng-ethyl cellulose conjugate obtained in step (1), and the volatile oil inclusion product obtained in step (2) through high-speed ball milling to obtain the solid Dispersion, the ball milling speed is 100r/min, and the ball milling time is 1.5h.
实施例4Example 4
本实施例中，提供一种用于治疗颈椎病固体分散体的制备方法，所述制备方法包括以下步骤：In the present embodiment, a preparation method of a solid dispersion for the treatment of cervical spondylosis is provided, and the preparation method comprises the following steps:
(1)将三七380g粉碎成微粉，向三七粉末中加入乙基纤维素进行球磨得到一种三七-乙基纤维素结合物，所述三七粉末与乙基纤维素的质量比为1:0.7，所述球磨速度为110r/min，时间为0.5h；(1) pulverize 380g of Panax notoginseng into micropowder, add ethyl cellulose to the notoginseng powder and perform ball milling to obtain a notoginseng-ethyl cellulose combination, the mass ratio of the notoginseng powder and ethyl cellulose is 1:0.7, the ball milling speed is 110r/min, and the time is 0.5h;
(2)羌活1000g、威灵仙1000g提取挥发油，挥发油用倍他环糊精(1ml：2.1g)包结成包合物，提取挥发油之后的药材加水煎煮煎液滤过；药渣再加水煎煮1小时，滤过，合并二次滤液，备用；(2) Extract volatile oil from 1000g of Qianghuo and 1000g of Weilingxian, and encapsulate the volatile oil with betacyclodextrin (1ml: 2.1g) to form an inclusion complex, add water to decoct the medicinal materials after extracting the volatile oil and filter; add water to the medicinal residues Decoct for 1 hour, filter, combine the secondary filtrate, set aside;
(3)葛根950g、白芍950g加水煎煮二次，第一次1.5小时，第二次1小时，合并煎液，滤过，滤液与上述滤液合并，浓缩至相对密度为1.12(50℃)，加乙醇使含醇量达65％，搅匀，冷藏过夜，滤过，滤渣用65％乙醇洗涤一次，洗涤液滤过，与上述滤液合并，得到所述葛根、白芍滤液；(3) 950g of Radix Puerariae and 950g of Paeonia lactiflora were added and boiled twice, the first time was 1.5 hours, the second time was 1 hour, the decoction was combined, filtered, and the filtrate was combined with the above-mentioned filtrate, and concentrated to a relative density of 1.12 (50° C.) , add ethanol to make the alcohol content reach 65%, stir evenly, refrigerate overnight, filter, the filter residue is washed once with 65% ethanol, the washing solution is filtered, and combined with the above-mentioned filtrate to obtain the Pueraria lobata, Radix Paeoniae Alba filtrate;
(4)川芎800g、延胡索600g加乙醇加热回流提取二次，第一次2.5小时，第二次1.5小时，合并提取液，静置过夜，滤过，与步骤(2)、(3)中得到的滤液合并，得到一种混合滤液；(4) 800g of Chuanxiong, 600g of Corydalis Radix are added with ethanol and heated to reflux for extraction twice, the first time is 2.5 hours, the second time is 1.5 hours, the extracts were combined, left standing overnight, filtered, and obtained in steps (2) and (3) The filtrates were combined to obtain a mixed filtrate;
(5)将上述混合滤液在50℃水浴条件下加热搅拌3h，在真空度-0.03～-0.07M Pa条件下旋蒸除去部分乙醇，之后在喷雾干燥方式下去除溶剂得到清膏，将清膏置于烘箱中40℃干燥过夜后粉碎至200目，粉碎过程中按照质量比1:0.01分多次加入氧化镁，得到一种固体结合物；(5) The above mixed filtrate was heated and stirred for 3h under the condition of 50°C water bath, and part of ethanol was removed by rotary evaporation under the condition of vacuum degree of -0.03～-0.07MPa, and then the solvent was removed by spray drying to obtain a clear paste. After drying overnight at 40°C in an oven, it is pulverized to 200 mesh, and during the pulverization process, magnesium oxide is added multiple times according to a mass ratio of 1:0.01 to obtain a solid combination;
(6)将步骤(5)得到的固体结合物、步骤(1)得到的三七-乙基纤维素结合物，步骤(2)得到的挥发油包结物混合通过球磨混均得到所述固体分散体；所述球磨转速为120r/min，球磨时间为1.5h。(6) Mix the solid conjugate obtained in step (5), the notoginseng-ethyl cellulose conjugate obtained in step (1), and the volatile oil inclusion complex obtained in step (2) by ball milling to obtain the solid dispersion body; the ball milling speed is 120r/min, and the ball milling time is 1.5h.
实施例5Example 5
本实施例中，提供一种用于治疗颈椎病的缓释片剂，所述缓释片剂原料组成及配比如下：In the present embodiment, a sustained-release tablet for the treatment of cervical spondylosis is provided, and the raw material composition and proportioning ratio of the sustained-release tablet are as follows:
Figure PCTCN2021098700-appb-000001
Figure PCTCN2021098700-appb-000001
制备方法：称取实施例1所述固体分散体粉碎过100目筛，将处方量的海藻酸钠、改性淀粉混均后再分批次加入过筛后的固体分散体中，加入的过程中不断搅拌使其完全混均，最后加入处方量的硬脂酸镁之后混合10～12min，通过高速压片机压片得到所述缓释片剂。Preparation method: Weigh the solid dispersion described in Example 1 and pulverize it through a 100-mesh sieve, mix the sodium alginate and modified starch in the recipe quantity, and then add them to the sieved solid dispersion in batches. The process of adding Stir continuously to make it completely uniform, finally add the magnesium stearate of the recipe, mix for 10-12 minutes, and press the tablet by a high-speed tableting machine to obtain the sustained-release tablet.
实施例6Example 6
本实施例中，提供一种用于治疗颈椎病的缓释片剂，所述缓释片剂原料组成及配比如下：In the present embodiment, a sustained-release tablet for the treatment of cervical spondylosis is provided, and the raw material composition and proportioning ratio of the sustained-release tablet are as follows:
Figure PCTCN2021098700-appb-000002
Figure PCTCN2021098700-appb-000002
Figure PCTCN2021098700-appb-000003
Figure PCTCN2021098700-appb-000003
制备方法：称取实施例1所述固体分散体粉碎过100目筛，将处方量的海藻酸、改性淀粉混均后再分批次加入过筛后的固体分散体中，加入的过程中不断搅拌使其完全混均，最后加入处方量的硬脂酸镁之后混合13min，通过高速压片机压片得到所述缓释片剂。Preparation method: Weigh the solid dispersion described in Example 1 and pulverize it through a 100-mesh sieve, mix the alginic acid and modified starch in the recipe amount, and then add them to the sieved solid dispersion in batches. Continuously stirring to make it completely mixed, finally adding the prescribed amount of magnesium stearate and then mixing for 13 minutes, and then compressed by a high-speed tableting machine to obtain the sustained-release tablet.
实施例7Example 7
本实施例中，提供一种用于治疗颈椎病的缓释片剂，所述缓释片剂原料组成及配比如下：In the present embodiment, a sustained-release tablet for the treatment of cervical spondylosis is provided, and the raw material composition and proportioning ratio of the sustained-release tablet are as follows:
Figure PCTCN2021098700-appb-000004
Figure PCTCN2021098700-appb-000004
制备方法：称取实施例1所述固体分散体粉碎过100目筛，将处方量的海藻酸、微晶纤维素混均后再分批次加入过筛后的固体分散体中，加入的过程中不断搅拌使其完全混均，最后加入处方量的硅酸镁铝之后混合20min，通过旋转式压片机压片得到所述缓释片剂。Preparation method: Weigh the solid dispersion described in Example 1 and pulverize it through a 100-mesh sieve, mix the alginic acid and microcrystalline cellulose of the recipe amount, and then add it to the sieved solid dispersion in batches. The process of adding Stir continuously to make it completely uniform, finally add the prescribed amount of magnesium aluminum silicate and mix for 20 minutes, and press the tablet by a rotary tableting machine to obtain the sustained-release tablet.
实施例8Example 8
本实施例中，提供一种用于治疗颈椎病的缓释胶囊，所述缓释胶囊原料组成及配比如下：In the present embodiment, a slow-release capsule for the treatment of cervical spondylosis is provided, and the raw material composition and proportion of the slow-release capsule are as follows:
实施例1所述固体分散体          35.0gThe solid dispersion described in Example 1 35.0g
西黄蓍胶                       0.8gGum tragacanth 0.8g
硅酸镁铝                       0.6gMagnesium Aluminum Silicate 0.6g
制备方法：称取实施例1所述固体分散体粉碎过100目筛，将处方量的海藻酸、西黄蓍胶混合20min，装胶囊0.5g每粒。Preparation method: Weigh the solid dispersion described in Example 1 and pulverize it through a 100-mesh sieve, mix the alginic acid and tragacanth in the recipe amount for 20 minutes, and pack 0.5 g of each capsule.
对比例1Comparative Example 1
三七350g粉碎成微粉；羌活1000g、威灵仙1000g提取挥发油，挥发油用倍他环糊精(1ml：3.3g)包结成包结物，煎液滤过；药渣再加水煎煮1小时，滤过，合并二次滤液，备用；葛根950g、白芍950g加水煎煮二次，第一次1.5小时，第二次1小时，合并煎液，滤过，滤液与上述滤液合并，浓缩至相对密度为1.12(50℃)，加乙醇使含醇量达60％，搅匀，冷藏过夜，滤过，滤渣用60％乙醇洗涤一次，洗涤液滤过，与上述滤液合并，回收乙醇,浓缩至相对密度为1.26(50℃)的清膏；川芎800g、延胡索600g加乙醇加热回流提取二次，第一次2小时，第二次1小时，合并提取液，静置过夜，滤过，滤液回收乙醇，浓缩至相对密度为1.26(50℃)的清膏；与上述清膏合并，混匀，加入三七微粉及挥发油倍他环糊精包结物、糊精，制成1000g颗粒，得到一种颗粒剂。350g of Panax notoginseng was crushed into micropowder; 1000g of Qianghuo and 1000g of Weilingxian were used to extract volatile oil, and the volatile oil was wrapped with betacyclodextrin (1ml: 3.3g) to form inclusions, and the decoction was filtered; the medicinal residues were decocted with water for 1 hour , filtered, merged the secondary filtrate, standby; 950g of Pueraria lobata, 950g of white peony root were added and boiled twice, the first 1.5 hours, the second time 1 hour, combined the decoction, filtered, and the filtrate was combined with the above-mentioned filtrate, concentrated to The relative density is 1.12 (50°C), add ethanol to make the alcohol content reach 60%, stir well, refrigerate overnight, filter, wash the filter residue once with 60% ethanol, filter the washing solution, combine with the above filtrate, recover ethanol, and concentrate To a clear paste with a relative density of 1.26 (50°C); 800 g of Chuanxiong and 600 g of Corydalis Radix are added with ethanol and heated and refluxed to extract twice, the first time is 2 hours, the second time is 1 hour, the extracts are combined, left standing overnight, filtered, and the filtrate Recover ethanol, and concentrate it to a clear paste with a relative density of 1.26 (50° C.); combine with the above-mentioned clear paste, mix well, add Panax notoginseng micropowder and volatile oil beta-cyclodextrin inclusion compound and dextrin to prepare 1000g granules to obtain a granule.
对比例2Comparative Example 2
本实施例中，提供一种固体分散体，所述固体分散体，将三七微粉按照质量比1:0.6与羟丙基纤维素混合，其余设置方式与实施例1中相同。In this embodiment, a solid dispersion is provided, wherein the solid dispersion is made by mixing Panax notoginseng micropowder with hydroxypropyl cellulose in a mass ratio of 1:0.6, and the rest of the setting methods are the same as those in Embodiment 1.
对比例3Comparative Example 3
本实施例中，提供一种固体分散体，所述固体分散体的制备中，步骤(5)得到的清膏置于烘箱中40℃干燥过夜后粉碎至200目，之后与步骤(1)得到的三七-乙基纤维素结合物，步骤(2)得到的挥发油包结物混合通过高速球磨混均得到所述固体分散体。其余步骤设置方式与实施例1中相同。In this embodiment, a solid dispersion is provided. In the preparation of the solid dispersion, the clear paste obtained in step (5) is dried in an oven at 40° C. overnight, pulverized to 200 mesh, and then obtained in step (1). The notoginseng-ethylcellulose combination, the volatile oil inclusions obtained in step (2) are mixed by high-speed ball milling to obtain the solid dispersion. The rest of the steps are set in the same manner as in Example 1.
实施例9Example 9
以下针对实施例1-4所述固体分散体，实施例5-8所述缓释制剂及对比例1-3 所述药物制剂的体外释药性能进行考察：The in vitro drug release properties of the solid dispersions described in Examples 1-4, the sustained-release preparations described in Examples 5-8 and the pharmaceutical preparations described in Comparative Examples 1-3 are investigated below:
1.体外释药性能1. In vitro drug release properties
选取颈痛颗粒中标志性成分人参皂苷Rg1，人参皂苷Rb1，三七皂苷R1进行体外药物释放性能考察，所述体外释药采用《中国药典》2010版而不附录溶出度测定法对实施例1-4中固体分散体，对比例1-3中所述制剂的释放度进行测定，释放介质为人工肠液。每组实施例中精确称定称量5份待测物置于溶出杯中，每个时间点取样5ml进行测定，同时计算累积释放百分率，结果如附图1所示。Ginsenoside Rg1, ginsenoside Rb1, and Panax notoginseng saponin R1, which are the landmark components in Jingtong Granules, were selected for in vitro drug release performance investigation. For the solid dispersion in -4, the release degree of the preparation described in Comparative Examples 1-3 was measured, and the release medium was artificial intestinal fluid. In each group of examples, 5 parts of the analyte were accurately weighed and placed in the dissolution cup, 5ml was sampled at each time point for measurement, and the cumulative release percentage was calculated at the same time. The results are shown in Figure 1.
所述人参皂苷Rg1，人参皂苷Rb1，三七皂苷R1按照专利CN104887771A中所记载的方法进行测定。The ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1 are determined according to the method described in the patent CN104887771A.
从图1中可以看出，实施例1提供的固体分散体中三中活性成分三七皂苷Rg1、人参皂苷Rg1及人参皂苷Rb1成分在12h内都具有稳定的释放效果，其中三七皂苷Rg1的总释放量累积可以达到80％左右，证明上述活性成分在服用后12h的时间都能够实现持续稳定的释放，并且释放较为彻底。As can be seen from Figure 1, the three active ingredients in the solid dispersion provided in Example 1, notoginsenoside Rg1, ginsenoside Rg1 and ginsenoside Rb1 all have stable release effects within 12h, wherein the notoginsenoside Rg1 has a stable release effect. The cumulative release amount can reach about 80%, which proves that the above-mentioned active ingredients can achieve sustained and stable release within 12 hours after taking the drug, and the release is relatively complete.
从图1A中看出，对比例1-3中人参皂苷Rg1总体释放量不如实施例1，对比例1中的颗粒在6h达到50％的释放量之后，之后的速度速度显著减慢，可以认为对比例1中的颗粒有效作用时间约为4～6h，对比例2中的缓释制剂相比对比例1具有一定的缓释效果，但其释放速度在6h之后出现了明显的减慢，最终释放量仅有65％。对比例3中的缓释制剂在4～8h出现了突释现象，说明对比例3中的制剂可能不稳定导致三七皂苷Rg1溶出速度突然加快。It can be seen from Figure 1A that the overall release amount of ginsenoside Rg1 in Comparative Examples 1-3 is not as good as that in Example 1. After the particles in Comparative Example 1 reach 50% of the released amount in 6 hours, the subsequent speed is significantly slowed down. It can be considered that The effective action time of the granules in Comparative Example 1 is about 4 to 6 hours. Compared with Comparative Example 1, the sustained-release preparation in Comparative Example 2 has a certain sustained-release effect, but its release rate is significantly slowed down after 6 hours. The release amount is only 65%. The sustained-release preparation in Comparative Example 3 showed a burst release phenomenon in 4-8 hours, indicating that the preparation in Comparative Example 3 may be unstable, resulting in a sudden acceleration of the dissolution rate of Panax notoginseng saponins Rg1.
2.不同组分释药性能2. Drug release properties of different components
本实施例中，还针对颈痛产品质量检测指标物质的释放量进行了检测，检测结果如下表1所示；In the present embodiment, the release amount of the index substance for neck pain product quality detection was also detected, and the detection results are shown in Table 1 below;
表1 固体分散体中各成分的累积释放率(％)Table 1 Cumulative release rate (%) of each component in solid dispersion
Figure PCTCN2021098700-appb-000005
Figure PCTCN2021098700-appb-000005
从表1中记载的数据可以看出，对比例1采用现有颈痛颗粒制备方法制备的颗粒剂，其中各项成分在6h已经完成了主要释药过程，6h到12h阶段药物释放量明显下降，药物释放速率也随之下降。实施例1中提供的固体分散体其中各项有效成分在12h的释放量总量均超过了对比例1，并且在2～6h及6～12h阶段具有大体相当的释放量。该结果证明了本发明提供的固体分散体能够同时促进该组方中不同成分的释放，能够整体提高各项药物的释放效果。From the data recorded in Table 1, it can be seen that the granules prepared by the existing Neck Pain granules preparation method in Comparative Example 1, in which each component has completed the main drug release process within 6h, and the drug release amount dropped significantly from 6h to 12h. , the drug release rate also decreased. In the solid dispersion provided in Example 1, the total release amount of each active ingredient in 12h exceeds that of Comparative Example 1, and the release amount is roughly equivalent in 2-6h and 6-12h stages. This result proves that the solid dispersion provided by the present invention can simultaneously promote the release of different components in the formula, and can improve the release effect of each drug as a whole.
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims (9)

  1. 一种治疗颈椎病的固体分散体，其特征在于，所述固体分散体制备方法如下：将三七粉与乙基纤维素混合得到三七-乙基纤维素结合物；A solid dispersion for the treatment of cervical spondylosis, characterized in that, the preparation method of the solid dispersion is as follows: mixing Panax notoginseng powder and ethyl cellulose to obtain a notoginseng-ethyl cellulose combination;
    所述羌活、威灵仙提取其中的挥发油与倍他环糊精得到包合物，剩余的药材煎煮过滤得到滤液；The volatile oil and beta cyclodextrin are extracted from the Qiang Huo and Wei Lingxian to obtain an inclusion compound, and the remaining medicinal materials are decocted and filtered to obtain a filtrate;
    葛根、白芍加水煎煮后浓缩，加入乙醇搅拌过滤得到滤液部分，将所述羌活、威灵仙滤液及葛根、白芍滤液以及川芎、延胡索的醇提液混合得到一种混合滤液，去除所述混合滤液的溶剂得到清膏，将所述清膏与氧化镁混合粉碎得到固体结合物；Pueraria lobata and Radix Paeoniae Alba are boiled with water and concentrated, add ethanol, stir and filter to obtain a filtrate part, mix the Qianghuo, Wei Lingxian filtrate and the alcohol extracts of Pueraria lobata, Paeonia lactiflora filtrate and Chuanxiong, Corydalis to obtain a mixed filtrate, remove all the filtrate. The solvent of the mixed filtrate obtains a clear paste, and the clear paste is mixed and pulverized with magnesium oxide to obtain a solid combination;
    将所述三七-乙基纤维素结合物、包合物及固体结合物混合均匀得到所述固体分散体。The solid dispersion is obtained by uniformly mixing the notoginseng-ethylcellulose combination, the inclusion compound and the solid combination.
  2. 如权利要求1所述用于治疗颈椎病的固体分散体，其特征在于，所述三七、羌活、威灵仙、葛根、白芍、川芎及延胡索的质量比为35～38：100：100：95：95：80～85：60～65。The solid dispersion for treating cervical spondylosis according to claim 1, wherein the mass ratio of the Panax notoginseng, Qianghuo, Weilingxian, Pueraria, Baishao, Chuanxiong and Corydalis is 35-38:100:100 : 95:95:80～85:60～65.
  3. 如权利要求1所述用于治疗颈椎病的固体分散体，其特征在于，所述三七粉为微粉或超微粉，目数为200目及以上；The solid dispersion for the treatment of cervical spondylosis according to claim 1, wherein the Panax notoginseng powder is a micropowder or an ultrafine powder, and the mesh number is 200 meshes and above;
    或，所述三七粉与乙基纤维素的加入比例为1:0.5～0.7；Or, the adding ratio of the notoginseng powder and ethyl cellulose is 1:0.5～0.7;
    或，所述三七与乙基纤维素通过球磨混合；优选的，所述球磨混合的速率为80～120r/min，时间为0.4～0.5h。Or, the notoginseng and ethyl cellulose are mixed by ball milling; preferably, the mixing speed of the ball milling is 80-120 r/min, and the time is 0.4-0.5 h.
  4. 如权利要求1所述用于治疗颈椎病的固体分散体，其特征在于，所述羌活、威灵仙提取挥发油之后的药材加水煎煮2～4次，并将数次的煎煮液合并过滤得到所述滤液；The solid dispersion for treating cervical spondylosis according to claim 1, characterized in that the medicinal materials after the volatile oil extracted from Qianghuo and Weilingxian are decocted with water for 2 to 4 times, and the decoction liquids for several times are combined and filtered. to obtain the filtrate;
    或，所述葛根、白芍加水煎煮后浓缩，加入乙醇搅拌过滤得到滤液部分具体步骤如下：将葛根、白芍加水煎煮2～4次，将数次煎煮液合并并过滤得到滤液， 将所述滤液浓缩至密度为1.10～1.15，向浓缩后的滤液中加入乙醇至溶液中乙醇浓度达到60～70％，搅拌后过滤得到滤液部分；Or, the pueraria root and white peony root are decocted with water and then concentrated, and the ethanol is added to stir and filter to obtain the filtrate. The specific steps are as follows: the pueraria root and white peony root are decocted with water for 2 to 4 times, and the decocting liquids are combined and filtered to obtain the filtrate, Concentrating the filtrate to a density of 1.10-1.15, adding ethanol to the concentrated filtrate until the ethanol concentration in the solution reaches 60-70%, stirring and filtering to obtain a filtrate part;
    或，所述川芎、延胡索的醇提液制备方法如下：向川芎、延胡索中加入乙醇回流提取2～4次，合并数次回流的提取液，过滤得到滤液。Or, the preparation method of the alcohol extract of Ligusticum chuanxiong and Corydalis Radix is as follows: adding ethanol to Ligusticum chuanxiong and Corydalis Rhizoma for 2 to 4 times of reflux extraction, combining the extracts refluxed for several times, and filtering to obtain a filtrate.
  5. 如权利要求1所述用于治疗颈椎病的固体分散体，其特征在于，所述所述羌活、威灵仙滤液及葛根、白芍滤液以及川芎、延胡索的醇提液混合后在水浴条件下加热搅拌一段时间得到所述混合溶液；The solid dispersion for the treatment of cervical spondylosis according to claim 1, characterized in that, the filtrate of Qianghuo, Weilingxian, pueraria, filtrate of white peony root, and the alcohol extract of Chuanxiong and Corydalis are mixed under water bath conditions. Heating and stirring for a period of time to obtain the mixed solution;
    优选的，所述水浴温度为45～50℃；Preferably, the temperature of the water bath is 45-50°C;
    优选的，所述水浴时间为3～3.5h。Preferably, the water bath time is 3-3.5h.
  6. 如权利要求1所述用于治疗颈椎病的固体分散体，其特征在于，所述混合滤液通过减压蒸馏除去部分溶剂及溶剂中的乙醇，干燥得到所述清膏；The solid dispersion for the treatment of cervical spondylosis according to claim 1, wherein the mixed filtrate is distilled under reduced pressure to remove part of the solvent and ethanol in the solvent, and dried to obtain the clear paste;
    优选的，所述减压蒸馏的真空度为-0.03～-0.07MPa；Preferably, the vacuum degree of the vacuum distillation is -0.03～-0.07MPa;
    优选的，所述干燥的方式包括但不限于采用喷雾干燥、真空干燥或冷冻干燥。Preferably, the drying method includes, but is not limited to, spray drying, vacuum drying or freeze drying.
  7. 如权利要求1所述用于治疗颈椎病的固体分散体，其特征在于，所述去除溶剂后得到清膏之后还包括对清膏进行干燥处理的步骤，所述干燥在40～45℃烘干处理；The solid dispersion for treating cervical spondylosis according to claim 1, characterized in that, after removing the solvent to obtain the clear paste, it further comprises the step of drying the clear paste, and the drying is dried at 40-45° C. deal with;
    或，所述清膏与氧化镁的质量比为1:0.01～0.02；Or, the mass ratio of the clear paste and magnesium oxide is 1:0.01～0.02;
    或，所述清膏与氧化镁的混合方式如下：将称量好的氧化镁分批次加入清膏中通过粉碎机进行粉碎；Or, the mixing mode of the clear paste and the magnesium oxide is as follows: the weighed magnesium oxide is added to the clear paste in batches and pulverized by a pulverizer;
    或，所述固体结合物、三七-乙基纤维素结合物及挥发油包合物通过球磨混合均匀；优选的，所述球磨转速为100～130r/min，时间为1～1.5h。Or, the solid conjugate, the notoginseng-ethylcellulose conjugate and the volatile oil inclusion complex are uniformly mixed by ball milling; preferably, the ball milling speed is 100-130 r/min, and the time is 1-1.5 h.
  8. 权利要求1-7任一项所述用于治疗颈椎病的固体分散体在制备抗颈椎病 缓释制剂中的应用；优选的，所述抗颈椎病缓释制剂为口服剂型，所述口服剂型包括但不限于颗粒剂、片剂、胶囊剂、散剂、丸剂。Application of the solid dispersion for treating cervical spondylosis according to any one of claims 1-7 in the preparation of an anti-cervical spondylosis sustained-release preparation; preferably, the anti-cervical spondylosis sustained-release preparation is an oral dosage form, and the oral dosage form Including but not limited to granules, tablets, capsules, powders, and pills.
  9. 权利要求8所述用于治疗颈椎病的固体分散体在制备抗颈椎病缓释制剂中的应用，其特征在于，所述抗颈椎病缓释制剂中包括权利要求1-7任一项所述固体分散体及药学上所必须的辅料；The application of the solid dispersion for treating cervical spondylosis according to claim 8 in the preparation of an anti-cervical spondylosis sustained-release preparation, characterized in that the anti-cervical spondylosis sustained-release preparation includes the application of any one of claims 1-7 Solid dispersions and pharmaceutically necessary excipients;
    优选的，所述抗颈椎病缓释制剂为片剂，所述片剂中包括所述固体分散体，还包括粘合剂及润滑剂；Preferably, the anti-cervical spondylosis sustained-release preparation is a tablet, and the tablet includes the solid dispersion, and also includes a binder and a lubricant;
    进一步的，所述润滑剂为包括但不限于改性淀粉、硬质酸钠、硅铝酸镁中的一种或几种的混合；Further, the lubricant is a mixture including but not limited to one or more of modified starch, sodium stearate, and magnesium aluminosilicate;
    进一步的，所述粘合剂为包括但不限于西黄蓍胶、壳聚糖、海藻酸、海藻酸钠中的一种或几种的组合；Further, the binder is one or more combinations including but not limited to gum tragacanth, chitosan, alginic acid, and sodium alginate;
    更进一步的，所述片剂中包括所述固体分散体、改性淀粉及硬脂酸镁；Further, the tablet includes the solid dispersion, modified starch and magnesium stearate;
    更进一步的，所述片剂中包括所述固体分散体、海藻酸、改性淀粉及硬脂酸镁；Further, the tablet includes the solid dispersion, alginic acid, modified starch and magnesium stearate;
    在一些具体的实施方式中，所述片剂中包括所述固体分散体、海藻酸、微晶纤维素及硅酸镁铝；In some specific embodiments, the solid dispersion, alginic acid, microcrystalline cellulose and magnesium aluminum silicate are included in the tablet;
    在一些具体的实施方式中，所述抗颈椎病缓释制剂为胶囊剂，所述胶囊剂包括所述固体分散体、西黄蓍胶及硅酸镁铝；In some specific embodiments, the anti-cervical spondylosis sustained-release preparation is a capsule, and the capsule includes the solid dispersion, tragacanth and magnesium aluminum silicate;
    或，所述抗颈椎病缓释制剂中包括所述固体分散体、其他具有抗颈椎病活性的成分或辅助抗颈椎病活性的成分，及药学上所必须的辅料；Or, the anti-cervical spondylosis sustained-release preparation includes the solid dispersion, other components with anti-cervical spondylosis activity or auxiliary anti-cervical spondylosis active components, and pharmaceutically necessary excipients;
    优选的，所述其他具有辅助抗颈椎病活性的成分包括但不限于抗炎药物、镇痛药物及营养神经型药物。Preferably, the other ingredients with adjuvant anti-cervical spondylosis activity include but are not limited to anti-inflammatory drugs, analgesic drugs and trophic neurotrophic drugs.
PCT/CN2021/098700 2020-08-06 2021-06-07 Solid dispersion for treating cervical spondylosis and use thereof in preparation of sustained-release preparation WO2022028084A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010782706.3 2020-08-06
CN202010782706.3A CN111939131B (en) 2020-08-06 2020-08-06 Solid dispersion for treating cervical spondylosis and application of solid dispersion in preparation of sustained-release preparation

Publications (1)

Publication Number Publication Date
WO2022028084A1 true WO2022028084A1 (en) 2022-02-10

Family

ID=73331475

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/098700 WO2022028084A1 (en) 2020-08-06 2021-06-07 Solid dispersion for treating cervical spondylosis and use thereof in preparation of sustained-release preparation

Country Status (2)

Country Link
CN (1) CN111939131B (en)
WO (1) WO2022028084A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111939131B (en) * 2020-08-06 2022-04-22 山东明仁福瑞达制药股份有限公司 Solid dispersion for treating cervical spondylosis and application of solid dispersion in preparation of sustained-release preparation
CN113398119A (en) * 2021-07-30 2021-09-17 山东明仁福瑞达制药股份有限公司 Pharmaceutical composition and application of ereoxib in preparation of medicament for resisting cervical spondylotic radiculopathy

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1446569A (en) * 2003-03-24 2003-10-08 于少华 Medicament for treating cervical spondylosis and preparation method thereof
CN101697988A (en) * 2009-10-30 2010-04-28 重庆科瑞制药有限责任公司 Taste hiding composition and application thereof in Xuesaitong chewable tablet
WO2014201637A1 (en) * 2013-06-19 2014-12-24 上海中医药大学附属龙华医院 Compound preparation for treating cervical spondylosis with radiculopathy and preparation method therefor
CN104887771A (en) * 2014-03-06 2015-09-09 山东明仁福瑞达制药股份有限公司 Medicinal preparation for treating nerve-root cervical spondylopathy, and preparation method and quality detection method thereof
CN111939131A (en) * 2020-08-06 2020-11-17 山东明仁福瑞达制药股份有限公司 Solid dispersion for treating cervical spondylosis and application of solid dispersion in preparation of sustained-release preparation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1446569A (en) * 2003-03-24 2003-10-08 于少华 Medicament for treating cervical spondylosis and preparation method thereof
CN101697988A (en) * 2009-10-30 2010-04-28 重庆科瑞制药有限责任公司 Taste hiding composition and application thereof in Xuesaitong chewable tablet
WO2014201637A1 (en) * 2013-06-19 2014-12-24 上海中医药大学附属龙华医院 Compound preparation for treating cervical spondylosis with radiculopathy and preparation method therefor
CN104887771A (en) * 2014-03-06 2015-09-09 山东明仁福瑞达制药股份有限公司 Medicinal preparation for treating nerve-root cervical spondylopathy, and preparation method and quality detection method thereof
CN111939131A (en) * 2020-08-06 2020-11-17 山东明仁福瑞达制药股份有限公司 Solid dispersion for treating cervical spondylosis and application of solid dispersion in preparation of sustained-release preparation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
31 May 2007, CN, ISBN: 978-7-5019-5885-6, article LING, PEIXUE: "Application of Powder Science in Pharmacy", pages: 168 - 170, XP009534120 *
ZHANG, ZHAOWANG: "Traditional Chinese Medicine Pharmacy, First Edition", 31 January 2003, CHINA PRESS OF TRADITIONAL CHINESE MEDICINE, CN, article "Solid Dispersion Technology", pages: 496 - 498, XP009534119 *

Also Published As

Publication number Publication date
CN111939131B (en) 2022-04-22
CN111939131A (en) 2020-11-17

Similar Documents

Publication Publication Date Title
WO2022028084A1 (en) Solid dispersion for treating cervical spondylosis and use thereof in preparation of sustained-release preparation
CN100536832C (en) Hemostatic notoginseng chewing tablet and preparation method thereof
CN1824012A (en) Perfect major supple mentation fast dispersion solid preparation and its making method
CN1171624C (en) Method for preparing Chinese medicine Liuwei Dihuang preparation
CN1814195B (en) Chinese medicine composition for treating gynecopathy and its preparation method thereof
CN1709326A (en) Method for preparing concentrated pill for treating mammary gland proliferation disease
CN1823959A (en) Heart vessel free flowing dispersion tablet and its preparation method
CN111821337B (en) Process for preparing pharmaceutical composition
CN115227795A (en) Compound medicine for treating HPV persistent infection and preparation method and application thereof
US20240307458A1 (en) Medicine composition for treatment of bone and joint diseases originated from medicinal materials and the process for producing thereof
CN101491628B (en) Lycium-rehmannia preparation preparation method
CN1814176B (en) Chinese medicinal composition for treating tuberculosis and its preparation method
CN113876877A (en) Micro traditional Chinese medicine tablet and preparation method thereof
CN102178891B (en) Chinese medicinal dispersible tablets for treating gastritis and preparation method thereof
CN100522238C (en) Pain-relieving and abdominal mass-eliminatnig bolus and its preparation
CN101926926B (en) Traditional Chinese medicinal preparation for treating rheumatic arthritis and chronic infectious arthritis
CN101269137B (en) Traditional Chinese medicine composition for treating hemorrhoid
CN1698855A (en) Powder with ass-hide glue and Chinese angelica root and its preparation method
CN112076276B (en) Pharmaceutical composition for treating allergic rhinitis and preparation method thereof
CN113769046B (en) Traditional Chinese medicine composition for treating intestinal metaplasia, preparation method and application
CN1733191A (en) Capsule for warming uterus and promoting pregnancy and process for preparing the same
CN101194963B (en) Process for preparing medicine for treating headache
CN101647930A (en) Peltate leaf perhexiline oral cavity disintegrating tablet and preparation method thereof
CN1456245A (en) Preparation of tablets for profuse menstruation
CN107441313B (en) Traditional Chinese medicine composition and medicine for treating ovarian reserve function decline and preparation method thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21852190

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21852190

Country of ref document: EP

Kind code of ref document: A1