CN116270699A - Three-party preparation, preparation method and application - Google Patents
Three-party preparation, preparation method and application Download PDFInfo
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- CN116270699A CN116270699A CN202310215086.9A CN202310215086A CN116270699A CN 116270699 A CN116270699 A CN 116270699A CN 202310215086 A CN202310215086 A CN 202310215086A CN 116270699 A CN116270699 A CN 116270699A
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- sodium
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- 238000002360 preparation method Methods 0.000 title claims abstract description 113
- 239000003814 drug Substances 0.000 claims abstract description 50
- 239000011734 sodium Substances 0.000 claims abstract description 38
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 38
- 239000000463 material Substances 0.000 claims abstract description 33
- 229960004748 abacavir Drugs 0.000 claims abstract description 28
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 22
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 19
- UXCAQJAQSWSNPQ-XLPZGREQSA-N Alovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](F)C1 UXCAQJAQSWSNPQ-XLPZGREQSA-N 0.000 claims abstract description 17
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- WMHSRBZIJNQHKT-FFKFEZPRSA-N abacavir sulfate Chemical compound OS(O)(=O)=O.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 WMHSRBZIJNQHKT-FFKFEZPRSA-N 0.000 claims description 24
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 2
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- 238000004090 dissolution Methods 0.000 description 8
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- 108010019625 Atazanavir Sulfate Proteins 0.000 description 2
- MCRNHLQVPJEMSQ-UHFFFAOYSA-N C(C=CC(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)[Na] Chemical compound C(C=CC(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)[Na] MCRNHLQVPJEMSQ-UHFFFAOYSA-N 0.000 description 2
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- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
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- 108020004414 DNA Proteins 0.000 description 1
- XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 description 1
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- UGWQMIXVUBLMAH-IVVFTGHFSA-N [(1s,4r)-4-[2-amino-6-(cyclopropylamino)purin-9-yl]cyclopent-2-en-1-yl]methanol;4-amino-1-[(2r,5s)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 UGWQMIXVUBLMAH-IVVFTGHFSA-N 0.000 description 1
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- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
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- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
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- 230000036737 immune function Effects 0.000 description 1
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- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
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- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 1
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- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a three-part preparation, a preparation method and application thereof, relates to the technical field of medicines, and aims to solve the problems of poor drug administration and high production cost when medicines with different mechanisms are used in combination. The three-party preparation comprises 0.2 to 0.3 percent of alovudine, 53 to 55 percent of abacavir, 4 to 5 percent of sodium, and 40 to 43 percent of auxiliary materials. The preparation method is used for preparing the three-part preparation. The three-party preparation, the preparation method and the application provided by the invention are used for increasing the compliance of the patient in the drug administration process, so that the process of taking the drug by the patient is easier.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a three-part preparation, a preparation method and application.
Background
HIV, human immunodeficiency virus (Human Immunodeficiency Virus), was first discovered in the United states in 1981 as a lentivirus (lentivirus) infecting cells of the human immune system, a retrovirus. The HIV virus targets the most important CD4T lymphocytes in the immune system of the human body, destroys the cells in large amounts, and causes the human body to lose immune function, so that the human body is susceptible to various diseases, and can develop malignant tumors, ultimately leading to AIDS (AIDS, acquired immunodeficiency syndrome).
Because HIV is very prone to mutation and attacks the human immune system, single drugs cannot control the proliferation of viruses in humans well, and methods for treating aids generally combine drugs with different mechanisms.
However, patients with aids who currently use combinations of several drugs with different mechanisms need to take several drugs separately. So that the patient has poor compliance in taking the medicine and the process of taking the medicine is difficult.
Disclosure of Invention
The invention aims to provide a three-part preparation, a preparation method and application thereof, and aims at the combined medication of AIDS patients, and the compliance of the medication of the patients is increased during the medication, so that the process of taking the medication by the patients is easier.
In order to achieve the above object, the present invention provides the following technical solutions:
in a first aspect, the invention provides a three-part preparation, which comprises 0.2-0.3% of alovudine, 53-55% of abacavir, 4-5% of doravir and 40-43% of auxiliary materials.
Compared with the prior art, the three-way preparation provided by the embodiment of the invention comprises the alzvudine, the abacavir and the dortezovir. Wherein, the alzvudine is an artificially synthesized nucleoside analogue, the abacavir is a nucleoside reverse transcriptase inhibitor, and the dortefravir is an integrase inhibitor. Because the three-way preparation of the embodiment of the invention comprises the alzvudine, the abacavir and the dortezovir, after the preparation of the oral pharmaceutical preparation, a patient only needs to take one drug orally during treatment, and the effect of treating the patient suffering from the AIDS infection by the combined drug can be achieved. In addition, the times of administration to patients after the preparation of the three-way preparation are reduced, and the administration of one medicine is not needed to be carried out after the administration of the other medicine, so that the administration to patients is more convenient. Meanwhile, the three-party preparation in the embodiment of the invention contains nucleoside reverse transcriptase inhibitor and integrase inhibitor, wherein the mass percentage of the alzvudine is 0.2-0.3%, the mass percentage of the abacavir is 53-55%, the mass percentage of the dorameavir is 4-5%, and the mass percentage of the auxiliary materials is 40-43%. Within the mass percentage range, the tablet weight or the capsule content weight of the obtained three-way preparation is smaller, and the dissolution rate is better. In addition, during the process production, the auxiliary materials can be jointly used by the alzvudine, the abacavir and the dortezovir, so that the use amount of the auxiliary materials is reduced, and only one production device is needed, so that the loss of the production device is reduced, and the production cost and the energy consumption are reduced.
Therefore, the three-party preparation provided by the embodiment of the invention aims at the combined medication of the AIDS patients, and increases the medication compliance of the patients during the medication, so that the process of taking the medicine by the patients is easier.
In a second aspect, the present invention also provides a method for preparing a three-part formulation, comprising:
mixing and granulating the alzvudine, the abacavir sulfate, the sodium dortefravir and auxiliary materials to obtain a premix;
the premix is formulated into a three-part formulation.
Compared with the prior art, the beneficial effects of the preparation method of the three-party preparation provided by the invention are the same as those of the three-party preparation of the first aspect, and the description is omitted here.
In a third aspect, a method of treating an immunodeficiency disorder in a human is provided.
Compared with the prior art, the beneficial effects of the application of the three-party preparation in the medicine for treating the human immunodeficiency diseases are the same as those of the three-party preparation in the first aspect, and the description is omitted here.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention and do not constitute a limitation on the invention. In the drawings:
fig. 1 shows a flowchart of a method for preparing the three-part formulation in this example.
Detailed Description
In order to make the technical problems, technical schemes and beneficial effects to be solved more clear, the invention is further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Furthermore, the terms "first," "second," and the like, are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. In the description of the present invention, the meaning of "a plurality" is two or more, unless explicitly defined otherwise. The meaning of "a number" is one or more than one unless specifically defined otherwise.
Human immunodeficiency virus, also known as AIDS virus, AIDS (AcquiredImmune Deficiency Syndrome, AIDS) is the last stage of infection by human immunodeficiency virus. During the AIDS period, HIV infection can cause various opportunistic infections and tumors, and the complications can influence the healthy life of people and even threaten life, so that the HIV can cause people to panic. Currently, aids virus diseases can be treated by antiretroviral drug combination therapy. Although the existing antiretroviral therapy cannot cure HIV infection, the existing antiretroviral therapy can inhibit viral replication, recover the immune system of a human body, enhance and restore the capability of resisting opportunistic infections and cancers.
Azvudine, a reverse transcriptase inhibitor of human immunodeficiency virus (Human Immunodeficiency Virus, HIV), is known under the chemical name 1- (4-azido-2-deoxy-2-fluoro-beta-D-ribofuranosyl) cytosine and has the structural formula:
clinically, the azlocarban is taken as an artificially synthesized nucleoside analogue, can be phosphorylated in cells to become an active 5' -triphosphate metabolite (namely the azlocarban triphosphate), and can inhibit the activity of recombinant HIV reverse transcriptase, so that the synthesis of a DNA chain of viruses is stopped, and the azlocarban can be taken as a new-generation medicine for treating AIDS.
Abacavir sulfate Wei Hua is named (1S, cis) -4- [ 2-amino-6- (cyclopropylamino) -9H-purin-9-yl ] -2-cyclopentene-1-methanol sulfate, and the Abacavir sulfate exists in the form of sulfate in the preparation, and has the following structural formula:
abacavir sulfate is white to off-white powder, is dissolved in water, has an anti-HIV effect, is successfully developed by Glaxo-Wellcom, inc. of Gelanin, U.S. Food and Drug Administration (FDA) in 1998, is approved for marketing, and is sold under the trade name Ziagen, which is a Nucleoside Reverse Transcriptase Inhibitor (NRTI) and is an inactive prodrug like other nucleoside reverse transcriptase inhibitors, is converted into an active metabolite, carbotriphosphates, in a human body by cytokinase, is an analogue of deoxychemical book guanosine triphosphate (dGTP), competes with the latter or integrates and intercalates into viral DNA, inhibits the activity of HIV reverse transcriptase, causes defects in the integrated pseudonucleotide, and stops replication of the viral DNA.
Sodium entecavir has the chemical name (4 r,12 as) -9- { [ (2, 4-difluorophenyl) methyl ] carbamoyl } -4-methyl-6, 8-dioxo-3, 4,6,8,12 a-hexahydro-2H-pyrido [1',2':4,5] pyrazine [2,1-b ] [1,3] oxazin-7-enol having the following structural formula:
however, patients with aids who currently use combinations of several drugs with different mechanisms need to take several drugs separately. So that the patient has poor compliance in taking the medicine and the process of taking the medicine is difficult. In addition, in the industrial production, a plurality of production lines are required for various pharmaceutical preparations, so that the loss of production equipment is increased, and the production cost is also increased.
In view of the above problems, the embodiments of the present invention further provide an application of the three-way preparation in preparing a medicament for treating human immunodeficiency diseases, so that the number of times of administration to a patient is reduced when treating human immunodeficiency diseases, and the administration to the patient is convenient without taking one medicament after taking the other medicament. Meanwhile, the three-party preparation contains the alzvudine, the abacavir and the doravir, so that the loss of production equipment and the production cost and the energy consumption can be reduced in the process of producing and preparing the three-party preparation. It is understood that the human immunodeficiency disease may be AIDS. The following is a detailed description of the three-part formulation and the preparation method from two points of view in conjunction with examples.
The three-party preparation provided by the embodiment of the invention mainly comprises the components of the alzvudine, the abacavir and the dortezovir and also comprises auxiliary materials. Wherein, the mass percentage of the alzvudine is 0.2-0.3%, the mass percentage of the abacavir is 53-55%, the mass percentage of the doramevir sodium is 4-5%, and the mass percentage of the auxiliary materials is 40-43%. It is understood that the dosage form of the three-part formulation may be a solid dosage form, which may include a tablet, granule or capsule or other solid formulation, without limitation. When the solid dosage form is a tablet, the three-way formulation of the present embodiments further includes a coating layer, which may be a film coating layer, which may be a gastric-soluble film coating material.
The three-way preparation provided by the embodiment of the invention comprises the alzvudine, the abacavir and the dortezovir. Wherein, the alzvudine is an artificially synthesized nucleoside analogue, the abacavir is a nucleoside reverse transcriptase inhibitor, and the dortefravir is an integrase inhibitor. Because the three-way preparation of the embodiment of the invention comprises the alzvudine, the abacavir and the dortezovir, after the preparation of the oral pharmaceutical preparation, a patient only needs to take one drug orally during treatment, and the effect of treating the patient suffering from the AIDS infection by the combined drug can be achieved. In addition, the times of administration to patients after the preparation of the three-way preparation are reduced, and the administration of one medicine is not needed to be carried out after the administration of the other medicine, so that the administration to patients is more convenient. Meanwhile, the three-party preparation in the embodiment of the invention contains nucleoside reverse transcriptase inhibitor and integrase inhibitor, wherein the mass percentage of the alzvudine is 0.2-0.3%, the mass percentage of the abacavir is 53-55%, the mass percentage of the dorameavir is 4-5%, and the mass percentage of the auxiliary materials is 40-43%. Within the mass percentage range, the tablet weight or the capsule content weight of the obtained three-way preparation is smaller, and the dissolution rate is better. In addition, during the process production, the auxiliary materials can be jointly used by the alzvudine, the abacavir and the dortezovir, so that the use amount of the auxiliary materials is reduced, and only one production device is needed, so that the loss of the production device is reduced, and the production cost and the energy consumption are reduced.
Therefore, the three-party preparation provided by the embodiment of the invention aims at the combined medication of AIDS patients, and increases the medication compliance of the patients during the medication, so that the process of taking the medicine by the patients is easier, and only a single production line is needed during industrial production, thereby reducing the loss of production equipment and reducing the production cost.
In one possible implementation, when the solid dosage form of the embodiment of the present invention is a tablet, the tablet weight of the tablet is 1.2g to 1.21g, and when the solid dosage form is a capsule, the content weight of a single capsule is 1.2g to 1.21g. The tablet weight or the weight of the content of the capsule in the embodiment of the invention is 1.2 g-1.21 g, and the tablet is smaller, so that the number of patients taking the medicine can be reduced during the administration, the compliance of the patients taking the medicine is also increased, and the process of the patients taking the medicine is easier.
In an alternative, the particle size distribution (Particle Size Distribution, PSD) D90 of the Azvudine in the three-way formulation of the present embodiment is between 5 μm and 50 μm. The particle size distribution reflects the percentage of particles of different particle size distribution in the powder sample in the total amount of particles. Wherein D90 represents: the particle size distribution corresponding to a sample with a cumulative particle size distribution number of 90% is physically defined as having a particle size distribution of less than or greater than 50% of its particles. When the particle size distribution of the alzhifu is in the range, the adhesion of the alzhifu surface is reduced, electrostatic adsorption is weakened, and aggregation is not easy to occur, so that when the alzhifu and tenofovir disoproxil are mixed, mixing and sieving can be performed smoothly, the sieving difficulty is reduced, the sieving time is shortened, and the situation that the sieving appears that the mixing blocks the sieve holes or is blocked in the sieve holes is avoided.
In one example, the particle size distribution D90 of the Azvudine of the present invention may also be 5-40 μm. In another example, the particle size distribution D90 of the azloc in the embodiment of the present invention may be 5 μm to 30 μm.
In an exemplary embodiment of the three-way formulation, the adjuvant includes one or more of a filler, an adhesive, a disintegrant, and a lubricant.
As for the filler, the filler is introduced into the alzvudine, the abacavir and the doravir, and can comprise one or more of microcrystalline cellulose, lactose and mannitol, preferably one or two of microcrystalline cellulose and lactose, so that the three-party preparation can be ensured to reach the quality or volume standard for manufacturing solid dosage forms.
As the binder, the binder includes one or two of pregelatinized starch, povidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose.
For the lubricant, the lubricant comprises one or two of stearate and talcum powder, wherein the stearate comprises one or more of magnesium stearate, sodium stearyl fumarate and calcium stearate.
As for the disintegrant, the disintegrant includes one or more of crospovidone, croscarmellose sodium and sodium carboxymethyl starch, preferably one or two of croscarmellose sodium and sodium carboxymethyl starch.
The mass ratio of the filler, the binder, the disintegrating agent and the lubricant is (10-50): (2-20): (1-20): (0.2-6). Of course, the mass ratio of the filler, the binder, the disintegrating agent and the lubricant may be (10-40): (2-10): (2-10): (0.5-5).
Fig. 1 shows a flowchart of a method for preparing the three-part formulation in this example.
As shown in fig. 1, the present invention further provides a preparation method of the three-part preparation, which comprises:
step 101: and mixing the albevudine, the abacavir and the dortevir with auxiliary materials, granulating to obtain a premix.
In one example, the dry granules may be obtained by mixing the alzvudine, abacavir and dortevir with the filler, binder and disintegrant, and then placing the mixture into a wet granulator to prepare a soft material, and drying the wet granules in a fluidized bed. And adding the sieved lubricant to mix to obtain a premix. In another example, the albefovir, abacavir, and dortevir may be mixed with fillers, binders, disintegrants, and lubricants and then placed into a dry granulator for granulation to obtain a premix. In other examples, the mixture of the alzvudine, abacavir and dortevir, the filler, the binder and part of the disintegrating agent may be granulated by a top-spray granulator to obtain whole granules, and the lubricant obtained after sieving may be added to mix to obtain a premix. It will be appreciated that embodiments of the present invention may employ any of the three modes described above to obtain a premix, and that direct compression and fluid bed processes may also be employed to prepare the three-part formulation. Regardless of the granulation mode employed, the three-way formulation of the present embodiments can be obtained.
Step 102: the premix is formulated into a three-part formulation.
For example: directly bagging to obtain granule, making capsule or making tablet by rotary tablet press. When the tablets are prepared, the tablets with target specifications can be prepared, or the tablets can be subjected to film coating to prepare coated tablets. The three-party preparation particles prepared according to the technical scheme of the invention have good flowing property, wide granulating process window, smooth sieving process, no blocking or clamping of the sieve, no elastic sheet and unstable sheet weight of the tablet, and easy realization of the challenges of high-speed tablet compression in industrialized mass production, and achieves the purposes of time saving and energy saving.
In order to verify the effect of the three-way preparation provided by the embodiment of the invention, the embodiment of the invention is exemplified by taking a solid dosage form as a tablet, and the embodiment of the invention is demonstrated by comparing the embodiment with a comparative example.
Example 1
The embodiment of the invention provides a three-party preparation, which comprises the following active ingredients of alovudine, abacavir sulfate and sodium dortefravir, wherein the granularity distribution D90 of the alovudine is as follows: 10 μm. The number of the three-way preparation in the embodiment of the invention is 1000, and table 1 shows the component proportion table of the three-way preparation in the embodiment of the invention.
Table 1A composition proportion Table of the three-way preparation of example I
The preparation method of the three-party preparation provided by the embodiment of the invention comprises the following steps:
first, a premix is prepared: mixing alzvudine, abacavir sulfate, sodium entecavir, mannitol, microcrystalline cellulose, povidone and sodium carboxymethyl starch, adding water into a wet granulator to prepare soft materials, obtaining wet granules, and drying the wet granules by a fluidized bed to obtain dry granules. And adding the sieved sodium stearyl fumarate, and mixing to obtain a premix.
Secondly, preparing a three-part tablet: tabletting the premix, and then coating the plain tablets in a coating machine by using a gastric-soluble film coating material to obtain the three-party tablets, wherein the weight of the target coating is increased by 2-4% of the weight of the tablet core.
Example two
The embodiment of the invention provides a three-party preparation, which comprises the following active ingredients of alovudine, abacavir sulfate and sodium dortefravir, wherein the granularity distribution D90 of the alovudine is as follows: 10 μm. The number of the three-way preparation in the embodiment of the invention is 1000, and the component proportion table of the three-way preparation in the second embodiment of the invention is shown in table 2.
Table 2 component proportion Table of the three-way preparation of example two
The preparation method of the three-way preparation provided by the second embodiment of the invention comprises the following steps:
first, a premix is prepared: mixing alzvudine, abacavir sulfate, sodium dortefravir, lactose, microcrystalline cellulose, hypromellose and sodium carboxymethyl starch, adding water into a wet granulator to prepare soft materials, obtaining wet granules, and drying the wet granules by a fluidized bed to obtain dry granules. And adding the sieved magnesium stearate, and mixing to obtain a premix.
Secondly, preparing a three-part tablet: tabletting the premix, and then coating the plain tablets in a coating machine by using a gastric-soluble film coating material to obtain the three-party tablets, wherein the weight of the target coating is increased by 2-4% of the weight of the tablet core.
Example III
The embodiment of the invention provides a three-party preparation, which comprises the following active ingredients of alovudine, abacavir sulfate and sodium dortefravir, wherein the granularity distribution D90 of the alovudine is as follows: 30 μm. The number of the three-way preparation in the embodiment of the invention is 1000, and the component proportion table of the three-way preparation in the embodiment of the invention is shown in table 3.
Table 3A three-part formulation of the example
| Material name | Component (A) | Quality of |
| Active ingredient 1 | Azvudine | 3g |
| Active ingredient 2 | Abacavir sulfate | 702g |
| Active ingredient 3 | Sodium Duolavir | 52.6g |
| Filler (B) | Microcrystalline cellulose | 329.4g |
| Adhesive agent | Povidone | 40g |
| Disintegrating agent | Croscarmellose sodium | 65g |
| Lubricant | Stearyl sodium fumarate | 10g |
The preparation method of the three-party preparation provided by the third embodiment of the invention comprises the following steps:
first, a premix is prepared: mixing alzvudine, abacavir sulfate, sodium entecavir, microcrystalline cellulose, povidone and croscarmellose sodium, adding water into a wet granulator to prepare soft materials, obtaining wet granules, and drying by a fluidized bed to obtain dry granules. And adding the sieved sodium stearyl fumarate, and mixing to obtain a premix.
Secondly, preparing a three-part tablet: tabletting the premix, and then coating the plain tablets in a coating machine by using a gastric-soluble film coating material to obtain the three-party tablets, wherein the weight of the target coating is increased by 2-4% of the weight of the tablet core.
Example IV
The embodiment of the invention provides a three-party preparation, which comprises the following active ingredients of alovudine, abacavir sulfate and sodium dortefravir, wherein the granularity distribution D90 of the alovudine is as follows: 50 μm. The number of the three-way preparation in the embodiment of the invention is 1000, and the component proportion table of the three-way preparation in the fourth embodiment of the invention is shown in table 4.
Table 4 component proportion Table of the three-way preparation of example IV
The preparation method of the three-party preparation provided by the fourth embodiment of the invention comprises the following steps:
first, a premix is prepared: mixing alzvudine, abacavir sulfate, sodium entecavir, mannitol, microcrystalline cellulose, povidone and sodium carboxymethyl starch, adding water into a wet granulator to prepare soft materials, obtaining wet granules, and drying the wet granules by a fluidized bed to obtain dry granules. And adding the sieved sodium stearyl fumarate, and mixing to obtain a premix.
Secondly, preparing a three-part tablet: tabletting the premix, and then coating the plain tablets in a coating machine by using a gastric-soluble film coating material to obtain the three-party tablets, wherein the weight of the target coating is increased by 2-4% of the weight of the tablet core.
Example five
The embodiment of the invention provides a three-party preparation, which comprises the following active ingredients of alovudine, abacavir sulfate and sodium dortefravir, wherein the granularity distribution D90 of the alovudine is as follows: 40 μm. The number of the three-way preparation in the embodiment of the invention is 1000, and the component proportion table of the three-way preparation in the embodiment of the invention is shown in table 5.
Table 5 Table of the composition ratios of the three-way preparation of example five
The preparation method of the three-party preparation provided by the fifth embodiment of the invention comprises the following steps:
first, a premix is prepared: mixing alzvudine, abacavir sulfate, sodium entecavir, mannitol, microcrystalline cellulose, povidone and sodium carboxymethyl starch, adding water into a wet granulator to prepare soft materials, obtaining wet granules, and drying the wet granules by a fluidized bed to obtain dry granules. And adding the sieved sodium stearyl fumarate, and mixing to obtain a premix.
Secondly, preparing a three-part tablet: tabletting the premix, and then coating the plain tablets in a coating machine by using a gastric-soluble film coating material to obtain the three-party tablets, wherein the weight of the target coating is increased by 2-4% of the weight of the tablet core.
Example six
The embodiment of the invention provides a three-party preparation, which comprises the following active ingredients of alovudine, abacavir sulfate and sodium dortefravir, wherein the granularity distribution D90 of the alovudine is as follows: 10 μm. The number of the three-way preparation in the embodiment of the invention is 1000, and the component proportion table of the three-way preparation in the sixth embodiment of the invention is shown in table 6.
Table 6 Table of the composition ratios of the three-way preparation of example six
The preparation method of the three-way preparation provided by the embodiment of the invention comprises the following steps:
first, a premix is prepared: mixing alzvudine, abacavir sulfate, sodium entecavir, mannitol, microcrystalline cellulose, povidone and sodium carboxymethyl starch, adding water into a wet granulator to prepare soft materials, obtaining wet granules, and drying the wet granules by a fluidized bed to obtain dry granules. And adding the sieved sodium stearyl fumarate, and mixing to obtain a premix.
Secondly, preparing a three-part tablet: tabletting the premix, and then coating the plain tablets in a coating machine by using a gastric-soluble film coating material to obtain the three-party tablets, wherein the weight of the target coating is increased by 2-4% of the weight of the tablet core.
Example seven
The embodiment of the invention provides a three-party preparation, which comprises the following active ingredients of alovudine, abacavir sulfate and sodium dortefravir, wherein the granularity distribution D90 of the alovudine is as follows: 5 μm. The number of the three-way preparation in the embodiment of the invention is 1000, and the component proportion table of the three-way preparation in the embodiment of the invention is shown in table 7.
Table 7A three-part formulation
The preparation method of the three-party preparation provided by the seventh embodiment of the invention comprises the following steps:
first, a premix is prepared: mixing alzvudine, abacavir sulfate, sodium entecavir, mannitol, microcrystalline cellulose, povidone and sodium carboxymethyl starch, adding water into a wet granulator to prepare soft materials, obtaining wet granules, and drying the wet granules by a fluidized bed to obtain dry granules. And adding the sieved sodium stearyl fumarate, and mixing to obtain a premix.
Secondly, preparing a three-part tablet: tabletting the premix, and then coating the plain tablets in a coating machine by using a gastric-soluble film coating material to obtain the three-party tablets, wherein the weight of the target coating is increased by 2-4% of the weight of the tablet core.
Comparative example one
The first comparative example of the present invention provides an Azvudine preparation, wherein the active ingredient selected is Azvudine, and the Azvudine particle size distribution D90 is: 20 μm. The number of the azloc preparations of the example of the present invention is 1000, and table 8 shows the component ratio table of the azloc preparation of comparative example one of the present invention.
Table 8 component proportion Table of the Azvudine preparation of comparative example one
| Material name | Component (A) | Quality of |
| Active ingredient 1 | Azvudine | 3g |
| Filler (B) | Microcrystalline cellulose | 97g |
| Adhesive agent | Povidone | 3g |
| Disintegrating agent | Croscarmellose sodium | 6g |
| Lubricant | Magnesium stearate | 1g |
The preparation method of the solid preparation provided by the first comparative example of the invention comprises the following steps:
first, a premix is prepared: mixing the alzvudine with microcrystalline cellulose, povidone and croscarmellose sodium, putting into a wet granulator to prepare a soft material, obtaining wet granules, and drying by a fluidized bed to obtain dry granules. And adding the sieved magnesium stearate, and mixing to obtain a premix.
Second, an alzvudine tablet is prepared: tabletting the premix, and then coating the plain tablets in a coating machine by using a gastric-soluble film coating material to obtain the Azvudine tablet, wherein the target coating weight gain is 2% -4% of the tablet core weight.
Comparative example two
The second comparative example of the present invention provides an abacavir formulation, wherein the active ingredient selected is abacavir sulfate. The number of the abacavir formulations of the comparative example of the present invention is 1000 tablets, and the composition ratio table of the abacavir formulation of the comparative example of the present invention is shown in Table 9.
Table 9 component proportion Table of Abacavir preparation of comparative example two
The preparation method of the abacavir preparation provided by the second comparative example comprises the following steps:
first, a premix is prepared: mixing abacavir sulfate with microcrystalline cellulose, hypromellose and carboxymethyl starch sodium, placing into a wet granulator for preparing soft materials to obtain wet granules, and drying by a fluidized bed to obtain dry granules. And adding the sieved magnesium stearate, and mixing to obtain a premix.
Secondly, preparing an abacavir tablet: tabletting the premix, and then coating the tablet with a gastric-soluble film coating material in a coating machine to obtain the abacavir tablet, wherein the target coating weight gain is 2% -4% of the tablet core weight.
Comparative example three
The invention provides a entecavir preparation, wherein the active ingredient selected by the entecavir preparation is sodium entecavir. The number of the entecavir formulations of the present invention comparative example was 1000 tablets, and table 10 shows the component proportioning table of the entecavir formulation of the present invention comparative example three.
Table 10 comparative example III A composition proportion table of Duolavir preparation
| Material name | Component (A) | Quality of |
| Active ingredient 1 | DuoteravirSodium salt | 52.6g |
| Filler (B) | Microcrystalline cellulose | 150g |
| Adhesive agent | Povidone | 12g |
| Disintegrating agent | Sodium carboxymethyl starch | 12g |
| Lubricant | Stearyl sodium fumarate | 3g |
The preparation method of the dorame preparation provided by the third comparative example comprises the following steps:
first, a premix is prepared: mixing the sodium entecavir with microcrystalline cellulose, povidone and sodium carboxymethyl starch, placing into a wet granulator to prepare soft materials, obtaining wet granules, and drying by a fluidized bed to obtain dry granules. And adding the sieved magnesium stearate, and mixing to obtain a premix.
Secondly, preparing a entecavir tablet: tabletting the premix, and then film-coating the plain tablets in a coating machine by using a gastric-soluble film coating material to obtain the doravir tablet, wherein the target coating weight gain is 2% -4% of the tablet core weight.
Comparative example four
The fourth comparative example of the present invention provides a three-way formulation comprising, as the active ingredients, sodium entecavir, abacavir sulfate and lamivudine. The number of the three-way preparation of the comparative example of the present invention is 1000, and the component proportion table of the three-way preparation of the fourth comparative example of the present invention is shown in table 11.
Table 11 component proportion Table of the three-way preparation of comparative example IV
The preparation method of the three-party preparation provided by the fourth comparative example comprises the following steps:
first, a premix is prepared: mixing lamivudine, abacavir sulfate and sodium adefovir dipivoxil with microcrystalline cellulose, mannitol, povidone and sodium carboxymethyl starch, placing into a wet granulator to prepare soft materials to obtain wet granules, and drying the wet granules by a fluidized bed to obtain dry granules. And adding the sieved sodium stearyl fumarate, and mixing to obtain a premix.
Secondly, preparing a three-part tablet: tabletting the premix, and then coating the plain tablets in a coating machine by using a gastric-soluble film coating material to obtain the three-party tablets, wherein the weight of the target coating is increased by 2-4% of the weight of the tablet core.
The three-party tablets prepared in the example and the solid preparations such as the tablet and the like are subjected to dissolution test to obtain dissolution rate, namely the dissolution rate and degree of the medicine in a specified solvent.
Table 12 the elution profiles of examples one to nine and comparative examples one to two were evaluated according to the elution profile guidelines (elution conditions: 900ml,37 ℃ C., 50rpm,45min in pH6.8 phosphate buffer with 0.5% SDS) and the results were as follows:
table 12 dissolution at 45min of examples one to seven and comparative examples one to four
From the table above, it can be seen that: the three-way formulation prepared in examples one to seven had similar dissolution rates of atazanavir and of the three-way formulation prepared in examples one to seven and of the three-way formulation of comparative example three, respectively, in 900ml of phosphate buffer pH6.8 containing 0.5% SDS, at 37℃and similar dissolution rates of atazanavir and of the three-way formulation of comparative example three. From the above, the three-way formulation of the present invention has similar absorption rates in vivo as those of the first, second, third and fourth comparative examples. Therefore, the three-way preparation obtained by the embodiment of the invention has smaller tablet weight or capsule content weight and similar dissolution rate to that of a single medicine. Therefore, aiming at the combined medication of the AIDS patients, the compliance of the medication of the patients is increased during the medication, so that the process of taking the medication by the patients is easier.
The foregoing is merely a specific embodiment of the invention, and it will be apparent that various modifications and combinations thereof can be made without departing from the spirit and scope of the invention. Accordingly, the specification and drawings are merely exemplary illustrations of the present invention as defined in the appended claims and are considered to cover any and all modifications, variations, combinations, or equivalents that fall within the scope of the invention. It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents. Any person skilled in the art can easily think of changes or substitutions within the technical scope of the present disclosure, and the present disclosure is intended to be covered by the present disclosure. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (10)
1. The three-party preparation is characterized by comprising 0.2-0.3% of alovudine, 53-55% of abacavir, 4-5% of sodium, and 40-43% of auxiliary materials.
2. The trigonal formulation of claim 1, wherein the dosage form of the trigonal formulation is a solid dosage form comprising a tablet or capsule.
3. The three-way formulation according to claim 2, wherein when the solid dosage form is a tablet, the tablet weight of the tablet is 1.2g to 1.21g, and when the solid dosage form is a capsule, the content weight of a single capsule is 1.2g to 1.21g.
4. The three-way formulation of claim 1, wherein the adjuvant comprises one or more of a filler, a binder, a disintegrant, and a lubricant.
5. The three-way formulation of claim 4, wherein when the adjuvant comprises a filler, the filler comprises one or more of microcrystalline cellulose, lactose, and mannitol; and/or the number of the groups of groups,
when the auxiliary material comprises a binder, the binder comprises one or more of pregelatinized starch, povidone, hypromellose and hypromellose; and/or the number of the groups of groups,
when the auxiliary material comprises a disintegrating agent, the disintegrating agent comprises one or more of crospovidone, croscarmellose sodium and sodium carboxymethyl starch; and/or the number of the groups of groups,
when the auxiliary material comprises a lubricant, the lubricant comprises one or more of stearate and talcum powder.
6. The three-part formulation according to claim 4, wherein when the auxiliary material comprises a filler, a binder, a disintegrant and a lubricant, the mass ratio of the filler, the binder, the disintegrant and the lubricant is (10 to 50): (2-20): (1-20): (0.2-6).
7. The three-way formulation according to any one of claims 1 to 6, wherein the particle size distribution D90 of the azloc is 5 to 50 μm.
8. A method of preparing the three-part formulation of any one of claims 1 to 7, comprising:
mixing and granulating the alzvudine, the abacavir sulfate, the sodium dortefravir and auxiliary materials to obtain a premix;
the premix is prepared into a three-way preparation, and the dosage form of the three-way preparation is a solid dosage form, and the solid dosage form comprises a tablet or a capsule.
9. The method of claim 8, wherein the granulating is one or more of dry granulating, wet granulating, or top-spraying granulating.
10. An application of a three-part preparation in preparing a medicament for treating human immunodeficiency diseases is provided.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310215086.9A CN116270699A (en) | 2023-03-07 | 2023-03-07 | Three-party preparation, preparation method and application |
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| CN202310215086.9A CN116270699A (en) | 2023-03-07 | 2023-03-07 | Three-party preparation, preparation method and application |
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