WO2022143168A1 - 含有吡咯喹啉醌三锂盐九水化合物的药物组合物、胶囊剂及其制备方法 - Google Patents

含有吡咯喹啉醌三锂盐九水化合物的药物组合物、胶囊剂及其制备方法 Download PDF

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WO2022143168A1
WO2022143168A1 PCT/CN2021/138255 CN2021138255W WO2022143168A1 WO 2022143168 A1 WO2022143168 A1 WO 2022143168A1 CN 2021138255 W CN2021138255 W CN 2021138255W WO 2022143168 A1 WO2022143168 A1 WO 2022143168A1
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pyrroloquinoline quinone
pharmaceutically acceptable
trilithium salt
salt nonahydrate
capsule
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French (fr)
Chinese (zh)
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张寰
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Shanghai Raising Pharmaceutical Co Ltd
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Shanghai Raising Pharmaceutical Co Ltd
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Priority to EP21913909.4A priority Critical patent/EP4268821A4/en
Priority to JP2023539383A priority patent/JP7729639B2/ja
Priority to US18/269,783 priority patent/US20240058323A1/en
Publication of WO2022143168A1 publication Critical patent/WO2022143168A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • 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
    • A61K9/4833—Encapsulating processes; Filling of capsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the invention belongs to the technical field of pharmaceutical preparations, in particular to a pharmaceutical composition containing a pyrroloquinoline quinone trilithium salt nonahydrate compound, a capsule containing the composition and a preparation method thereof.
  • the compound represented by formula (I) is pyrroloquinoline quinone trilithium salt nonahydrate, chemical name 4,5-dioxo-4,5-dihydro-1H-pyrrolo[2,3-f]quinoline- 2,7,9-Tricarboxylate lithium salt nonahydrate, molecular formula C 14 H 3 Li 3 N 2 O 8 9H 2 O, molecular weight 510.14, is a promising drug for the treatment of Parkinson's disease and senile dementia. drug candidates for neurodegenerative diseases.
  • Chinese invention patent applications 200910048873.9 and 201310270885.2 respectively disclose the lithium salt salt form and the nonahydrate crystal form of the pyrroloquinoline quinone compound.
  • PXRD powder X-ray diffraction
  • the study also found that the nonahydrate compound has a crystal water content of up to 31.8%, which is sensitive to temperature. The loss of crystal water occurs at 40 °C, and rapid and irreversible water loss occurs when the temperature is higher than 60 °C.
  • the crystalline API of pyrroloquinoline quinone trilithium salt nonahydrate has defects such as easy aggregation and agglomeration, low bulk density, poor fluidity, and easy adhesion to the surface of the equipment, it is necessary to increase the bulk density and fluidity by granulating methods to avoid Achieve the accuracy of the subsequent capsule filling process.
  • the study found that the process of wet granulation, drying, and solvent removal will cause the pyrroloquinoline quinone trilithium salt nonahydrate to partially or completely lose the crystal water, resulting in the change of the crystal form.
  • the dry granulation method does not require the use of solvents, which can avoid the risk of crystal form changes caused by heating.
  • pyrroloquinoline quinone trilithium salt nonahydrate is a metal salt containing a high proportion of crystal water. Like many metal salts, it is easy to form a rigid and hard structure under pressure. Dry granulation is a process in which drugs and excipients are mixed, first rolled into flakes, and then broken into granules. If the metal salt forms a rigid structure sheet after rolling, it will not only make subsequent processing difficult and reduce production efficiency, but also long-term rolling and repeated crushing will make the equipment heat up, affecting the pyrroloquinoline quinone trilithium salt nonahydrate compound crystal stability. In addition, forced granulation makes the prepared granules hard and also causes a decrease in the dissolution rate.
  • the present invention provides a pharmaceutical composition containing pyrroloquinoline quinone trilithium salt nonahydrate, a capsule containing the composition and a preparation method thereof, the pharmaceutical composition provided by the present invention, and Capsules containing the composition and the preparation method thereof can ensure that the crystal form of the pyrroloquinoline quinone trilithium salt nonahydrate compound has good stability and dissolution effect, and can ensure that each unit of the preparation has a higher drug content at the same time.
  • the dosage of excipients is reduced as much as possible, which is convenient for elderly patients to take, and improves the compliance of elderly patients with taking medicine.
  • the invention provides a pharmaceutical composition containing pyrroloquinoline quinone trilithium salt nonahydrate, the pharmaceutical composition comprising:
  • the pharmaceutically acceptable excipients include:
  • the pyrroloquinoline quinone trilithium salt nonahydrate is in crystal form, and the X-ray powder diffraction pattern of the pyrroloquinoline quinone trilithium salt nonahydrate represented by the 2 ⁇ diffraction angle is at 6.2° ⁇ 0.2°, 7.4° There are characteristic diffraction peaks at ⁇ 0.2°, 7.9° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • the pharmaceutically acceptable adjuvant also includes:
  • the other pharmaceutically acceptable adjuvants are selected from starch, pregelatinized starch, microcrystalline cellulose, lactose, lactose starch complex, lactose cellulose complex, mannitol, mannitol starch complex, sorbitol, polyvitamin. Ketone, copovidone, hypromellose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, magnesium stearate, stearyl fumarate One or more of sodium, talc, and stearic acid.
  • the colloidal silicon dioxide is 0.2 to 0.4 parts by weight; the other pharmaceutically acceptable auxiliary materials are 2.0 to 4.0 parts by weight.
  • the other pharmaceutically acceptable adjuvants include: 0.6 to 4 parts by weight of pregelatinized starch; 0.36 to 0.96 parts by weight of microcrystalline cellulose; 0 to 0.06 part by weight of magnesium stearate .
  • colloidal silicon dioxide can be added by internal addition or internal and external addition; the other pharmaceutically acceptable auxiliary materials can be added by internal addition or internal and external addition.
  • the weight ratio of the internal added colloidal silicon dioxide to the externally added colloidal silicon dioxide is greater than 3:1; using the internal and external addition method to add other pharmaceutically acceptable When adding other pharmaceutically acceptable excipients, the weight ratio of adding other pharmaceutically acceptable excipients and adding other pharmaceutically acceptable excipients is greater than 3:1.
  • the other pharmaceutically acceptable adjuvants that can be added by internal addition are selected from starch, lactose, microcrystalline cellulose, mannitol, croscarmellose sodium, copovidone, magnesium stearate
  • the other pharmaceutically acceptable adjuvants that can be added by addition method are selected from one or more of microcrystalline cellulose, croscarmellose sodium, magnesium stearate .
  • the present invention also provides a capsule containing pyrroloquinoline quinone trilithium salt nonahydrate, and the capsule containing pyrroloquinoline quinone trilithium salt nonahydrate comprises the pharmaceutical composition of the present invention.
  • the capsule material can be selected from any one of gelatin capsules, hypromellose capsules, pullulan capsules, and starch capsules.
  • the capsule material is hypromellose capsules.
  • the content of pyrroloquinoline quinone trilithium salt nonahydrate in each capsule is 5 mg to 100 mg.
  • the content of pyrroloquinoline quinone trilithium salt nonahydrate in each capsule is 20 mg to 75 mg.
  • the present invention also provides a method for preparing a capsule containing pyrroloquinoline quinone trilithium salt nonahydrate, which is used for preparing the capsule containing pyrroloquinoline quinone trilithium salt nonahydrate according to the present invention.
  • the preparation method is a method for preparing capsules by dry granulation.
  • the preparation method includes:
  • Dry granulation is carried out with the mixed pyrroloquinoline quinone trilithium salt nonahydrate crude drug and the pharmaceutically acceptable adjuvant, first rolled into flakes and then granulated into granules;
  • the granules are filled with capsules to obtain the capsules.
  • the preparation method includes:
  • Capsule filling is performed on the granules mixed with external pharmaceutically acceptable auxiliary materials to obtain the capsule.
  • the pharmaceutical composition containing pyrroloquinoline quinone trilithium salt nonahydrate, the capsule containing the composition and the preparation method thereof provided by the embodiments of the present invention have the following advantages:
  • the pharmaceutical composition containing pyrroloquinoline quinone trilithium salt nonahydrate provided by the present invention through the combined use of an appropriate proportion of colloidal silicon dioxide and an appropriate proportion of other pharmaceutically acceptable excipients, the use of colloidal silicon dioxide high
  • the specific surface area and low density (equivalent to containing a high proportion of air), combined with the dilution effect of other pharmaceutically acceptable excipients, effectively alleviated that the pyrroloquinoline quinone trilithium salt nonahydrate compound is easy to form rigid and difficult to granulate flakes due to dry granulation.
  • the resulting dry granulation flakes are loose and easy to granulate, which improves production efficiency and yield, and provides a possibility for commercial production scale-up.
  • due to the large specific surface area and good anti-sticking effect of colloidal silica it can better solve the problems of easy aggregation and agglomeration and easy adhesion to the surface of the equipment.
  • the pyrroloquinoline quinone trilithium salt nonahydrate compound capsule prepared by the composition of the present invention and the capsule preparation process thereof enables the pyrroloquinoline quinone trilithium salt nonahydrate compound crystal form to have better stability and dissolution effect.
  • the experimental results show that the capsules can be stored for a long time at 30 °C, and can maintain a good dissolution effect for a long time and after 6 months of acceleration under the environment of 25 °C, 60% relative humidity and 30 °C, 65% relative humidity. No related substances were detected, and the characteristic peaks and geometric topography of PXRD were consistent with 0 days, indicating that the capsules containing the pharmaceutical composition prepared by the process of the present invention had good chemical stability.
  • the proportion of the used excipients is reasonable, the use of excessive excipients is avoided, the prepared capsule is suitable for swallowing by elderly patients, convenient for elderly patients to take, and the compliance of elderly patients with medication is improved.
  • Fig. 1 is the microscope observation result of pyrroloquinoline quinone trilithium salt nonahydrate bulk drug substance
  • Fig. 2 is the dissolution curve of the capsule No.1 ⁇ No.4 of the prescription of Example 1;
  • Fig. 3 is the dissolution curve of No.5 ⁇ No.8 capsules of the prescription of Example 2;
  • Fig. 4 is the dissolution curve of No.9 ⁇ No.12 capsules of the prescription of Example 3;
  • Fig. 5 is the dissolution curve of No.13 ⁇ No.16 capsules of the prescription of Example 4.
  • Fig. 6 is the dissolution curve of the capsule No.1 ⁇ No.2 of the prescription of Comparative Example 1;
  • Fig. 7 is the dissolution curve of the capsule No.3 ⁇ No.6 of the prescription of Comparative Example 2;
  • Fig. 8 is the dissolution curve of No.7 ⁇ No.10 capsules of the prescription of Comparative Example 3;
  • Fig. 9 is the dissolution curve before and after the 6-month assessment of the stability of the formulation No. 3 capsule of Example 1 and the capsule No. 7 of the formulation of Example 2;
  • Fig. 10 shows the PXRD measurement results of the No. 3 capsule of the recipe of Example 1 and the capsule of No. 7 of the recipe of Example 2 before and after 6 months of examination.
  • the crystal water content of pyrroloquinoline quinone trilithium salt nonahydrate is as high as 31.8%, and it is sensitive to temperature, the loss of crystal water occurs when the temperature exceeds 40°C, and the rapid and irreversible water loss occurs when the temperature exceeds 60°C. .
  • the API of pyrroloquinoline quinone trilithium salt nonahydrate is short rod-shaped, and the drug particles are easy to aggregate into clusters (the microscope observation results are shown in Figure 1, the agglomerated drug particles are in the dotted circle). Defects such as low bulk density, poor fluidity, and easy adhesion to equipment surfaces.
  • Pyrroloquinoline quinone trilithium salt nonahydrate is a metal lithium salt. If the proportion of excipients in the prescription is low and the drug is not sufficiently diluted and dispersed, the sheet obtained by rolling is hard and not easy to be crushed (common to many metal salts). If it is repeatedly crushed at high speed, the frictional heat will also affect the stability of the hydrate.
  • the pharmaceutical composition containing pyrroloquinoline quinone trilithium salt nonahydrate provided by the present invention, by combining an appropriate proportion of colloidal silicon dioxide and an appropriate proportion of other pharmaceutically acceptable excipients, using The high specific surface area and low density of colloidal silica (equivalent to containing a high proportion of air), combined with the dilution effect of other pharmaceutically acceptable excipients, effectively alleviates the easy dry granulation of pyrroloquinoline quinone trilithium salt nonahydrate.
  • the obtained flakes Due to the defect of forming rigid flakes that are difficult to granulate, the obtained flakes are loose and easy to granulate after dry granulation, which improves production efficiency and yield, and provides a possibility for commercial production scale-up. At the same time, due to the large specific surface area and good anti-sticking effect of colloidal silica, it can better solve the problems of easy aggregation and agglomeration and easy adhesion to the surface of the equipment.
  • the pyrroloquinoline quinone trilithium salt nonahydrate compound capsule prepared by the composition of the present invention and the capsule preparation process thereof enables the pyrroloquinoline quinone trilithium salt nonahydrate compound crystal form to have better stability and dissolution effect.
  • the experimental results show that the capsules can be stored for a long time at 30 °C, and can maintain a good dissolution effect for a long time and after 6 months of acceleration under the environment of 25 °C, 60% relative humidity and 30 °C, 65% relative humidity. No related substances were detected, indicating that the capsule containing the pharmaceutical composition prepared by the process of the present invention has good chemical stability.
  • the proportion of the used excipients is reasonable, the use of excessive excipients is avoided, and the prepared capsule is suitable for swallowing by elderly patients, which is convenient for elderly patients to take, and improves the medication compliance of elderly patients.
  • the raw materials, samples, reagents and equipment used in the embodiments of the present invention are all commercially available products and can be purchased in the market.
  • the raw drug pyrroloquinoline quinone trilithium salt nonahydrate crystal can be prepared by referring to the preparation method in the Chinese invention patent authorization document CN103351387B (application number 201310270885.2, published on 2013.10.16), which will not be repeated here.
  • the pyrroloquinoline quinone trilithium salt nonahydrate prepared by the above preparation method has an X-ray powder diffraction pattern represented by the 2 ⁇ diffraction angle at 6.2° ⁇ 0.2°, 7.4° ⁇ 0.2°, 7.9° ⁇ 0.2°, 23.6° ⁇ The 0.2° position shows a characteristic diffraction peak.
  • the specifications and supplier information of excipients used in Examples 1 to 4 and Comparative Example 1 to Comparative Example 3 are as follows: colloidal silicon dioxide, pregelatinized starch (Starch 1500, Colorcon), microcrystalline cellulose (VIVAPUR 101 , JRS), magnesium stearate (MF2V, Liaoning Aoda), lactose (granulac200, MEGGLE), mannitol (160C, ROQUETTE), anhydrous calcium hydrogen phosphate (Fujicalin-SG, Fuji chemical), magnesium aluminum silicate ( Neusilin UFL2, Fuji chemical), croscarmellose sodium (Ac-Di-Sol, FMC BioPolymer); copovidone (VA64fine, BASF).
  • colloidal silica also known as micropowder silica gel or fumed silica
  • colloidal silica is usually prepared by reacting silicon tetrachloride in a hydrogen and oxygen flame (Chinese Pharmacopoeia 2020 Edition Four Colloidal Silica Items, page P719).
  • the English names of colloidal silica have different descriptions such as Colloidal Anhydrous Silica, Light Anhydrous Silicic Acid, Silica Colloidal Anhydrous, Colloidal Silicon Dioxide or Fumed Silica Powder.
  • the conventional dosage is 0.1% to 0.3% (Editor-in-Chief Fang Liang, "Pharmaceutics” 8th Edition, People's Health Publishing House, page 127).
  • the dosage is in the range of 0.1% to 1.0% (Raymond C Rowe, Paul J Sheskey, Marian E Quinn, ed., Handbook of Pharmaceutical Excipients, 6th Edition, published jointly by Pharmaceutical Press and the American Pharmacists Association, p186).
  • Example 1 to Example 4 Compositions, capsules and preparations containing pyrroloquinoline quinone trilithium salt nonahydrate
  • Example 1 (Prescription No. 1 to No. 4), Example 2 (Prescription No. 5 to No. 8), Example 3 (Prescription No. 9 to No. 12), Example 4 (Prescription No. 13) and the preparation method of prescription No.15):
  • Raw material pretreatment 30-mesh sieving treatment is performed on the pyrroloquinoline quinone trilithium salt nonahydrate raw material drug, and 40-mesh sieving treatment is performed on the auxiliary materials;
  • Dry granulation under the environment of temperature 15°C ⁇ 25°C and relative humidity 45% ⁇ 55%, add the pyrroloquinoline quinone trilithium salt nonahydrate API and all the auxiliary materials to the dry granulator.
  • dry granulation is carried out, and the granulation parameters are: rolling pressure 5.0MPa ⁇ 1.0MPa, feed speed 15rpm-30rpm, roller speed 4rpm-8rpm, and granulating with the equipment of 20 meshes;
  • Capsule filling Under the environment of temperature 15°C ⁇ 25°C and relative humidity 45% ⁇ 55%, calculate the actual filling amount according to the intermediate content and theoretical filling amount, and select the appropriate capsule specification. Place the qualified materials and hollow capsules in the powder tray and capsule tray of the capsule filling machine respectively, fill the capsules at a speed of 18,000 capsules/hour, and control the average filling volume difference of the capsules to be ⁇ 5.0% and a single capsule. The difference in loading volume is ⁇ 7.5%.
  • Packaging In the DPP80 automatic blister packaging machine, the filled capsules are packaged in double aluminum blister packaging at a speed of 1200 plates/hour.
  • Raw material pretreatment 30-mesh sieving treatment is performed on the pyrroloquinoline quinone trilithium salt nonahydrate raw material drug, and 40-mesh sieving treatment is performed on the auxiliary materials;
  • Dry granulation under the environment of temperature 15 °C ⁇ 25 °C, relative humidity 45% ⁇ 55%, add the pyrroloquinoline quinone trilithium salt nonahydrate crude drug and the added auxiliary materials to the dry granulation
  • dry granulation is carried out, and the granulation parameters are: rolling pressure 5.0MPa ⁇ 1.0MPa, feed speed 15rpm-30rpm, roller speed 4rpm-8rpm, and the equipment is equipped with a 20-mesh granulation;
  • Capsule filling Under the environment of temperature 15°C ⁇ 25°C and relative humidity 45% ⁇ 55%, calculate the actual filling amount according to the intermediate content and theoretical filling amount, and select the appropriate capsule specification. Place the qualified materials and hollow capsules in the powder tray and capsule tray of the capsule filling machine respectively, fill the capsules at a speed of 18,000 capsules/hour, and control the average filling volume difference of the capsules to be ⁇ 5.0% and a single capsule. The difference in loading volume is ⁇ 7.5%.
  • Comparative Example 1 Formulation No. 1 and Formulation No. 2
  • Comparative Example 2 Formulation No. 3 to No. 6
  • Comparative Example 3 Formulation No. 7 to No. 10.
  • Example 1 to Example 4 and Comparative Example 1 and Comparative Example 3 After dry granulation of the prepared pyrroloquinoline quinone trilithium salt nonahydrate flakes (thickness between 0.8mm and 1.0mm), 20g ⁇ 2g each, placed in the granulation equipment that comes with the dry granulation equipment, with the equipment set. It has a fixed speed (96 rpm, motor power is 0.2KW, one-way rotary granulation) and passes through a 20-mesh 316L stainless steel screen. The granulation time is fixed at 15min.
  • Granulation results From the results in Table 8 and Table 9, it can be seen that the granulation yields of the capsules No. 1 to No. 16 prepared according to Examples 1 to 4 are all greater than 90%.
  • the colloidal silicon dioxide is preferably 0.2 to 0.4 parts by weight, and the other pharmaceutically acceptable adjuvants are preferably 2.0 to 4.0 parts by weight, as in the example
  • the encapsulation yields of recipe No. 2 and No. 3 in recipe 1, recipe No. 7 in example 2, recipe No. 9 to No. 12 in example 3, and recipe No. 13 to No. 16 in example 4 were all greater than 97 %.
  • Comparative Example 1 Although the capsule of prescription No. 1 contains colloidal silicon dioxide, due to the addition of a certain proportion of other metal salts such as anhydrous calcium hydrogen phosphate, the material becomes hard and difficult to handle, and the whole grain is 15min. After that, the yield was only 46.1%.
  • the colloidal silica of the formulation No. 7 of the embodiment 2 is replaced with the same high specific surface area (300m 2 /g) and low bulk density (0.06 ⁇ 0.11g/cm 3 )
  • other metal salt UFL2 aluminum magnesium silicate with tap density (0.10 ⁇ 0.17g/cm 3 ) the whole grain yield decreased from 99.5% to 50.1%.
  • metal salt aluminum magnesium silicate can The effect of increasing the rigidity of the particles, while colloidal silica can play a role in counteracting or reducing the rigidity effect.
  • Comparative Example 3 the ratio of pyrroloquinoline quinone trilithium salt nonahydrate to colloidal silica was fixed at 1:0.16, and the ratio of other pharmaceutically acceptable excipients was changed to be lower than 1.0, such as prescription No. As shown in .7 and No.8, the yields after granulation were only 37.2% and 35.8%, respectively, indicating that in addition to colloidal silicon dioxide, it is also crucial to maintain the dosage of other pharmaceutically acceptable excipients to a certain proportion. .
  • Dissolution test conditions 900mL of hydrochloric acid solution at 37 ⁇ 0.2°C and pH 1.2 was used as the dissolution medium, and the rotation speed was 50 rpm.
  • the capsules were placed in the sinker and put into the dissolution cup. Filter through a 0.45 ⁇ m microporous membrane made of plain ester, and take the subsequent filtrate as the test solution.
  • the colloidal silica was replaced with the same one with extremely high specific surface area (300m 2 /g), low bulk density (0.06 ⁇ 0.11g/cm 3 ) and tap density (0.10 ⁇ 0.17 g/cm 3 ) of UFL2-type magnesium aluminum silicate, as a result, the cumulative dissolution of the prepared capsules after 20 min and 30 min was also reduced to 78.3% and 87.7%, respectively.
  • Determination method of related substances use octadecylsilane bonded silica gel as filler (TCI Kaseisorb LC ODS 2000, 4.6*150mm or equivalent chromatographic column); 10mM dipotassium hydrogen phosphate-15mM tetrabutylammonium bromide buffer Liquid (preparation method: take 2.28 g of dipotassium hydrogen phosphate trihydrate, 4.84 g of tetrabutylammonium bromide, dilute to 1 L with water, adjust the pH value to 7.4 with phosphoric acid) as mobile phase A, take acetonitrile as mobile phase B, press Table 9 performs gradient elution; flow rate: 1.0 mL/min, detection wavelength: 250 nm, column temperature: 30°C.

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PCT/CN2021/138255 2020-12-28 2021-12-15 含有吡咯喹啉醌三锂盐九水化合物的药物组合物、胶囊剂及其制备方法 Ceased WO2022143168A1 (zh)

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EP21913909.4A EP4268821A4 (en) 2020-12-28 2021-12-15 PHARMACEUTICAL COMPOSITION CONTAINING PYRROLOQUINOLINEQUINONETRILITHIUM SALT NONHYDRATE COMPOUND, CAPSULE AND MANUFACTURING PROCESS THEREOF
JP2023539383A JP7729639B2 (ja) 2020-12-28 2021-12-15 ピロロキノリンキノントリリチウム塩九水和物化合物を含む医薬組成物、カプセル剤およびその製造方法
US18/269,783 US20240058323A1 (en) 2020-12-28 2021-12-15 Pharmaceutical composition containing pyrroloquinoline quinone trilithium salt nonahydrate compound, capsule, and preparation method therefor

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