CN107213138B - Method and pharmaceutical composition for treating hypertension by timed release of drugs - Google Patents

Method and pharmaceutical composition for treating hypertension by timed release of drugs Download PDF

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CN107213138B
CN107213138B CN201710664741.3A CN201710664741A CN107213138B CN 107213138 B CN107213138 B CN 107213138B CN 201710664741 A CN201710664741 A CN 201710664741A CN 107213138 B CN107213138 B CN 107213138B
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dissolution
pellets
release phase
amount
pharmaceutical composition
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CN107213138A (en
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魏世峰
汪鹤龄
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Beijing Luo Nuo Qiang Shi Pharmaceutical Technology R&d Center Co ltd
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Beijing Luo Nuo Qiang Shi Pharmaceutical Technology R&d Center Co ltd
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    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

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  • Health & Medical Sciences (AREA)
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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to methods and pharmaceutical compositions for the timed release of drugs for the treatment of hypertension. In particular, the present invention relates to a pharmaceutical composition for timed release drug treatment of hypertension, in the form of pellets comprising a first release phase section and a second release phase section, wherein the pellets of the first release phase section comprise: an active drug, a diluent, a disintegrant, a binder, and optionally a coating layer; the pellets of the second release phase portion comprise: active drug, diluent, disintegrating agent, adhesive and coating layer for regulating drug release. The method for treating hypertension by releasing the medicine at fixed time and the medicine composition used in the method are an excellent tool for clinical hypertension time therapeutics.

Description

Method and pharmaceutical composition for treating hypertension by timed release of drugs
Technical Field
The invention belongs to the technical field of medicines, and particularly belongs to the technical field of preparations for treating hypertension by releasing medicines at regular time. In particular, the present invention relates to a method for treating hypertension with a time-release drug, and a pharmaceutical composition for use in the method for treating hypertension with the time-release drug. The method for treating hypertension by using the time release medicine and the pharmaceutical composition used in the method are an excellent tool for clinical time treatment of hypertension. The antihypertensive drug of the present invention is, for example, valsartan, amlodipine and pharmaceutically acceptable salts thereof, captopril and the like.
Background
The blood pressure of a human body shows rhythmic changes within 24 hours: blood pressure rapidly rises to a peak value within hours after waking in the early morning, and falls to a valley value in the middle-night to early morning. The morning peak phenomenon is one of two important features of blood pressure.
According to the research results of chronopharmacology in recent years, the heart rate and blood pressure of a person are in a low trough at night, so that the attack rate of angina and hypertension at the time is low, at the time, the medicine is basically not required to be provided in blood, and the heart rate and blood pressure of the person are increased within a few hours after waking in the morning, so that angina and hypertension are frequently generated at the time, and at the time, if a certain blood concentration peak value can be synchronously maintained in the blood, the attack of cardiovascular diseases can be effectively prevented and reduced.
Blood pressure is regulated by various factors in nerve body fluid, the activity of a sympathetic nervous system, the levels of renin, angiotensin II, aldosterone and the like are also changed rhythmically, and the activity of the substances is obviously increased in the early morning to be the main reason of morning peak phenomenon of blood pressure. Consistent with this, many clinical studies and meta-analyses have shown that cardiovascular and cerebrovascular events such as myocardial infarction, myocardial ischemia, sudden death, and stroke are all well in the early morning.
Understanding the rhythmic change rule of blood pressure and the relationship between the rhythmic change rule and cardiovascular and cerebrovascular events has important guiding significance for treating hypertension clinically. The ideal antihypertensive drug has good compliance, and can stably reduce blood pressure within 24 hours, remarkably reduce early blood pressure of patients, and ensure that the patients with hypertension safely pass the high-incidence period of cardiovascular and cerebrovascular events; can recover the normal blood pressure mode of the patient, reduce the blood pressure variability and effectively protect the functions of target organs. This is the "chronotherapy" of hypertension.
"chronotherapy" is a newer therapeutic concept. The time therapeutics aims at the time biological characteristics of human bodies, selects proper pharmaceutical preparations and reasonable administration time or a specific administration technology to ensure that the pharmaceutical action is consistent with the rhythm of diseases, thereby achieving the purposes of optimizing the treatment effect and reducing the adverse drug reactions. At present, researchers at home and abroad are actively developing antihypertensive drugs according to the time therapeutic principle of hypertension.
As for general preparations of captopril and other medicines, the captopril does not act through liver metabolism, is metabolized fast in vivo, takes effect within 15-30 minutes after oral administration, has a half-life period of about 2 hours, has a duration of only 4-8 hours, and can achieve a good blood pressure reduction effect only after being taken for a plurality of times in 1 day. At present, the captopril sustained release tablet is reported in research reports, such as the captopril sustained release tablet reported in the research on the three-dimensional dissolution characteristics and in-vivo and in-vitro correlation of the captopril sustained release tablet, which is compiled in the proceedings of the academy of Guangdong institute of medicine, 1997, 13(2), 73-74, Linhuaqing and the like, and aims to prolong the half-life period and reduce the medicine taking times of patients, but the delayed release of the captopril sustained release tablet cannot be controlled. At present, no captopril controlled release preparation capable of delaying release exists, which aims at the morning peak phenomenon; the current conventional captopril preparation is difficult to enable a hypertensive patient to avoid the dangerous early morning time, and the inconvenience of getting up to take the medicine in the early morning is brought to the life of the patient. Therefore, it is necessary to design a captopril controlled release preparation which is taken before sleep (9-11: 00 pm), and 3: 00 effective dose of medicine is released continuously, so that the action of the medicine is consistent with the rhythm of disease occurrence, and the hypertensive can safely pass the high-incidence period of the cardiovascular and cerebrovascular events. Thus, the dosage form is designed to delay release for 4-6 hours, preferably 5 hours, and then continue release for a period of time to delay the time of drug release and increase the duration of drug release.
The requirements also exist for other medicines, namely the medicines are not taken usually in the period from the time when the medicines are taken before sleep at night (9: 00-10: 00 evening) to the time when the medicines get up in the next morning, but the medicines are not taken in the period from 3: 00-4: the morning wake at around 00 hours is the period during which a booster dose is required. Therefore, it is important to provide a method for treating hypertension by releasing drugs with two drug-releasing phases at regular time from the late time to the early morning, for example, a part of the drugs is released in gastric juice within 1-2 hours after the drugs are taken, and then another part of the drugs is released under intestinal juice condition within 6-7 hours after the drugs are taken, so as to meet the requirement of drug administration in two time periods, which is still desired by the skilled person.
Disclosure of Invention
The invention aims to provide a method for treating hypertension by using a time release medicine and a pharmaceutical composition for the method for treating hypertension by using the time release medicine. The method for treating hypertension by timed release of a drug and the pharmaceutical composition used in the method of the present invention are expected to be excellent tools for chronotherapy of hypertension in clinical practice. Antihypertensive drugs such as valsartan, amlodipine and pharmaceutically acceptable salts thereof, captopril and the like which are involved in the method of treating hypertension according to the present invention.
To this end, the present invention provides in a first aspect a pharmaceutical composition for timed release drug therapy of hypertension, the pharmaceutical composition being in the form of pellets comprising a first release phase section and a second release phase section; wherein the content of the first and second substances,
the pellets of the first release phase portion comprise: an active drug, a diluent, a disintegrant, a binder, and optionally a coating layer;
the pellets of the second release phase portion comprise: active drug, diluent, disintegrating agent, adhesive and coating layer for regulating drug release.
The pharmaceutical composition according to any embodiment of the first aspect of the invention, wherein the active drug is a blood pressure lowering drug.
The pharmaceutical composition according to any embodiment of the first aspect of the invention, wherein the active drug is a blood pressure lowering agent selected from the group consisting of: valsartan, amlodipine and pharmaceutically acceptable salts thereof such as maleate, besylate, aspartate, mesylate, captopril and the like.
The pharmaceutical composition according to any embodiment of the first aspect of the present invention, wherein the active drug in the first release phase portion accounts for 30% to 50% of the total amount of the active drug in the pharmaceutical composition, and the active drug in the second release phase portion accounts for 50% to 70% of the total amount of the active drug in the pharmaceutical composition.
The pharmaceutical composition according to any embodiment of the first aspect of the present invention, wherein the diluent in the first release phase part is selected from the group consisting of: microcrystalline cellulose, starch, dextrin, lactose, dibasic calcium phosphate, and combinations thereof.
The pharmaceutical composition according to any embodiment of the first aspect of the present invention, wherein the diluent is present in the first release phase part in an amount of 30 to 80 parts by weight, for example 30 to 60 parts by weight, per 30 parts by weight of the active agent.
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, wherein the disintegrant in the first release phase portion is selected from the group consisting of: crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and combinations thereof.
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, wherein the weight of the disintegrant in the first release phase part is 5 to 30 parts by weight, for example 10 to 20 parts by weight, per 30 parts by weight of the active drug.
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, wherein the binder in the first release phase part is selected from the group consisting of: povidone, methylcellulose, ethylcellulose, carboxymethylcellulose, starch slurry, hypromellose, gelatin, polyethylene glycol, sodium alginate, water, ethanol, and combinations thereof. In one embodiment, the binder is selected from the group consisting of povidone, starch slurry, hypromellose, water, and combinations thereof. In one embodiment, the binder is selected from povidone, hypromellose, which is used in water formulated into binder solutions (such binder solutions typically used in the art have a concentration of typically 3-8%).
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, wherein the binder is present in the first release phase part in an amount of 2 to 10 parts by weight, for example 3 to 8 parts by weight, per 30 parts by weight of the active agent.
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, wherein the coating layer of the first release phase part is a coating layer capable of dissolving in the gastric acid environment. Examples of specific coating materials are Eudragit E, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and the like.
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, wherein the weight of the coating layer in the first release phase part is 10 to 30 parts by weight, for example 15 to 25 parts by weight, per 30 parts by weight of the active drug.
The pharmaceutical composition according to any embodiment of the first aspect of the present invention, wherein the pellets of the first release phase fraction have an average diameter of 0.2 to 2mm, such as 0.5 to 1.5mm, such as 0.5 to 1.2mm, such as 0.5 to 0.8 mm.
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, wherein the pellets of the first release phase fraction are eluted in four dissolution media at 30min in an amount of more than 80% of the content of the main drug in the pellets, as determined by dissolution test a below;
the procedure for the dissolution test method A is as follows: filling an appropriate amount of pellets corresponding to 50mg of an active drug (such as valsartan) into an empty capsule, respectively using a pH1.2 hydrochloric acid solution, a pH4.0 phosphate buffer (6.80 g of potassium dihydrogen phosphate is taken and dissolved in water to 1000mL, and the pH value is adjusted to 4.0 by phosphoric acid or sodium hydroxide) and a pH6.8 phosphate buffer (6.80 g of potassium dihydrogen phosphate and 0.90g of sodium hydroxide are taken and dissolved in water to 1000mL, the pH value is adjusted to 6.8), 1000mL of water is taken as a dissolution medium, the rotating speed is 100 revolutions per minute, operating according to the method, taking an appropriate amount of the solution at a specified time point, filtering, precisely taking an appropriate amount of a subsequent filtrate, quantitatively diluting the subsequent filtrate with the dissolution medium to prepare a solution containing about 16 mu g of the active drug in each 1mL, and measuring absorbance at a wavelength of 250nm according to an ultraviolet-visible spectrophotometry according to the first method of the general rule of the national regulation of "Chinese pharmacopoeia" 2015 edition; taking another appropriate amount of active drug reference substance, precisely weighing, adding dissolution medium to dissolve and quantitatively diluting to obtain solution containing 16 μ g per 1ml, measuring by the same method, and calculating dissolution amount of each capsule in different dissolution media.
It is essential that the pellets of the first release phase fraction of the present invention release the drug rapidly, which is a fraction of the drug that is effective rapidly after the formulation is taken, to produce the therapeutic effect of the conventional hypotensive drugs.
The pharmaceutical composition according to any embodiment of the first aspect of the present invention, wherein the diluent in the second release phase portion is selected from the group consisting of: microcrystalline cellulose, starch, dextrin, lactose, dibasic calcium phosphate, and combinations thereof.
The pharmaceutical composition according to any embodiment of the first aspect of the present invention, wherein the diluent is present in the second release phase part in an amount of 30 to 80 parts by weight, for example 30 to 60 parts by weight, per 50 parts by weight of the active agent.
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, wherein the disintegrant in the second release phase portion is selected from the group consisting of: crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and combinations thereof.
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, wherein the weight of the disintegrant in the second release phase part is 5 to 30 parts by weight, for example 10 to 20 parts by weight, per 50 parts by weight of the active drug.
The pharmaceutical composition according to any embodiment of the first aspect of the present invention, wherein the binder in the second release phase part is selected from the group consisting of: povidone, methylcellulose, ethylcellulose, carboxymethylcellulose, starch slurry, hypromellose, gelatin, polyethylene glycol, sodium alginate, water, ethanol, and combinations thereof. In one embodiment, the binder is selected from the group consisting of povidone, starch slurry, hypromellose, water, and combinations thereof. In one embodiment, the binder is selected from povidone, hypromellose, which is used in water formulated into binder solutions (such binder solutions typically used in the art have a concentration of typically 3-8%).
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, wherein the binder is present in the second release phase part in an amount of 2 to 10 parts by weight, for example 3 to 8 parts by weight, per 50 parts by weight of the active agent.
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, wherein the coating layer of the second release phase part is a coating layer that is insoluble in the gastric acid environment. For example, the coating material used for the coating layer is a gastric-soluble type coating material. Examples of typical coating materials are e.g. cellulose acetate phthalate, hypromellose phthalate (HPMCP), polyvinyl alcohol phthalate (PVAP), Eudragit L, Eudragit S, acrylic resin I, acrylic resin II, acrylic resin IV, methacrylic acid copolymers, etc.
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, wherein the weight of the coating layer in the second release phase part is 20 to 50 parts by weight, for example 20 to 40 parts by weight, per 50 parts by weight of the active drug.
The pharmaceutical composition according to any embodiment of the first aspect of the present invention, wherein the pellets of the second release phase fraction have an average diameter of 0.2 to 2mm, such as 0.5 to 1.5mm, such as 0.5 to 1.2mm, such as 0.5 to 0.8 mm.
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, wherein the pellets of the second release phase fraction are taken in appropriate amounts at2 hours, 3 hours, 4 hours respectively upon dissolution in four dissolution media as determined by dissolution method a, for determining the amount of dissolution at that point in time in each dissolution media, wherein:
the dissolution amount in two dissolution media of pH1.2 and pH4.0 at 4 hr is less than 10% of the main drug content in the pellet;
the dissolution amount in two dissolution media of pH6.8 and water at2 hours is less than 15% of the content of the main drug in the pellet;
the dissolution amount in two dissolution media of pH6.8 and water at 3 hours is more than 80% of the content of the main drug in the pellet.
The pellets of the second release phase fraction of the present invention release substantially no drug in a medium of low pH within 4 hours, only very small amounts within 2 hours in a neutral medium but are able to release the majority of the drug at 3 hours. Thus, the pellets of the second release phase part are not released when the drug passes through the stomach after administration (usually, 2 hours), only a tiny amount of the drug is released within 2 hours after entering the intestinal tract after 2 hours, and most of the drug can be released in about 3 hours in the intestinal tract, that is, the pellets of the second release phase part are mostly released after 5 hours after administration, and in the case of administration before bedtime (9: 00-10: 00 pm) in the usual evening, the drug in the pellets of the second release phase part is mostly released after 5 hours, so that 3: 00-4: the drug is absorbed into the blood before the arrival of about 00 morning waking hours to control the blood pressure rise of the morning waking hours.
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, wherein the amount of dissolution in each dissolution medium at that time point is determined by taking appropriate amounts of solutions at 0.5 hour, 2 hours, 3 hours, 4 hours, respectively, upon dissolution in four dissolution media, as determined by dissolution assay a, wherein:
the amount eluted at 0.5 hours in both dissolution media pH1.2 and pH4.0 is 90-120% (e.g. 90-110%) of the amount of drug in the first release phase portion of the pharmaceutical composition;
the amount eluted at 4 hours in both dissolution media pH1.2 and pH4.0 is 100-140% (e.g., 100-125%) of the amount of drug in the first release phase portion of the pharmaceutical composition;
the amount eluted at2 hours in both dissolution media pH6.8 and water is 100-140% (e.g. 100-130%) of the amount of drug in the first release phase portion of the pharmaceutical composition;
the amount of the extract in the two dissolution media of pH6.8 and water at 3 hr is more than 85% (such as more than 90%) of the amount of the Chinese medicinal materials in the pharmaceutical composition.
Thus, the pharmaceutical composition provided by the invention has two release stages in the whole gastrointestinal tract, wherein the first release stage can release a first part of drug but not release a second part of drug basically in the gastric juice, the medicament still does not release the drug basically between 2 hours after entering the intestinal tract, and more than 85% of the total dosage of the medicament can be released after about 3 hours, thereby providing the possibility of reducing the pressure by taking the medicament regularly at night and reducing the pressure by waking at morning. It has been surprisingly found that when a small amount of liquid paraffin as a coating aid (e.g. added in an amount of 1-3% by weight of the coating material, e.g. 2%) is added to the coating solution when coating the pellets of the second release phase fraction, the pellets of the second release phase fraction are capable of eluting less than 15% of the main drug content in the pellets within 2 hours and more than 80% of the main drug content in the pellets within 3 hours in both neutral dissolution media, ph6.8 and water. If this coating aid is not added, the resulting pellets of the second release phase fraction will mostly dissolve at1 hour in both neutral dissolution media ph6.8 and water. Therefore, in one embodiment of the present invention, the coating auxiliary agent is further included in the coating layer of the second phase-releasing part in an amount of 5 to 10% by weight of the coating material in the coating layer.
Further, the second aspect of the present invention provides a method for treating hypertension by timed release of a drug, which comprises administering to a hypertensive patient in need thereof a therapeutically effective amount of a pharmaceutical composition in the form of pellets comprising a first release phase part and a second release phase part before bedtime evening (which may be typically 9: 00-10: 00 evening); wherein the content of the first and second substances,
the pellets of the first release phase portion comprise: an active drug, a diluent, a disintegrant, a binder, and optionally a coating layer;
the pellets of the second release phase portion comprise: active drug, diluent, disintegrating agent, adhesive and coating layer for regulating drug release.
Alternatively, or in other words, the second aspect of the invention provides the use of the pharmaceutical composition, for example of any of the embodiments of any of the aspects of the invention, in the manufacture of a medicament for the timed release drug treatment of hypertension. For example, the timed release medicament for treating hypertension is to administer a therapeutically effective amount of the pharmaceutical composition to a hypertensive patient in need thereof before going to sleep at night (usually, 9: 00-10: 00 at night).
The method according to any embodiment of the second aspect of the invention, wherein the active drug is a blood pressure lowering drug.
The method according to any of the embodiments of the second aspect of the invention, wherein the active drug is a blood pressure lowering drug selected from the group consisting of: valsartan, amlodipine and pharmaceutically acceptable salts thereof such as maleate, besylate, aspartate, mesylate, captopril and the like.
The method according to any embodiment of the second aspect of the present invention, wherein the active drug in the first release phase fraction accounts for 30% to 50% of the total amount of active drug in the pharmaceutical composition, and the active drug in the second release phase fraction accounts for 50% to 70% of the total amount of active drug in the pharmaceutical composition.
The method according to any one of the embodiments of the second aspect of the present invention, wherein the diluent in the first release phase portion is selected from the group consisting of: microcrystalline cellulose, starch, dextrin, lactose, dibasic calcium phosphate, and combinations thereof.
The process according to any embodiment of the second aspect of the present invention, wherein the weight of the diluent in the first release phase part is 30 to 80 parts by weight, for example 30 to 60 parts by weight, per 30 parts by weight of the active drug.
The method according to any one of the embodiments of the second aspect of the present invention, wherein the disintegrant in the first release phase portion is selected from the group consisting of: crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and combinations thereof.
The process according to any embodiment of the second aspect of the present invention, wherein the weight of the disintegrant in the first release phase fraction is 5 to 30 parts by weight, for example 10 to 20 parts by weight, per 30 parts by weight of active drug.
The method according to any one of the embodiments of the second aspect of the present invention, wherein the binder in the first release phase part is selected from the group consisting of: povidone, methylcellulose, ethylcellulose, carboxymethylcellulose, starch slurry, hypromellose, gelatin, polyethylene glycol, sodium alginate, water, ethanol, and combinations thereof. In one embodiment, the binder is selected from the group consisting of povidone, starch slurry, hypromellose, water, and combinations thereof. In one embodiment, the binder is selected from povidone, hypromellose, which is used in water formulated into binder solutions (such binder solutions typically used in the art have a concentration of typically 3-8%).
The method according to any embodiment of the second aspect of the present invention, wherein the binder is present in the first release phase fraction in an amount of 2 to 10 parts by weight, such as 3 to 8 parts by weight, per 30 parts by weight of active drug.
The method according to any embodiment of the second aspect of the present invention, wherein the coating layer of the first release phase part is a coating layer capable of dissolving in the gastric acid environment. Examples of specific coating materials are Eudragit E, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and the like.
The process according to any embodiment of the second aspect of the present invention, wherein the weight of the coating layer in the first release phase fraction is 10 to 30 parts by weight, such as 15 to 25 parts by weight, per 30 parts by weight of active drug.
The process according to any embodiment of the second aspect of the present invention, wherein the pellets of the first release phase fraction have an average diameter of 0.2 to 2mm, such as 0.5 to 1.5mm, such as 0.5 to 1.2mm, such as 0.5 to 0.8 mm.
The method according to any of the embodiments of the second aspect of the present invention, wherein the pellets of the first release phase fraction are eluted in four dissolution media at 30min in an amount of more than 80% of the content of the main drug in the pellets, as determined by dissolution test a below;
the procedure for the dissolution test method A is as follows: filling an appropriate amount of pellets corresponding to 50mg of an active drug (such as valsartan) into an empty capsule, respectively using a pH1.2 hydrochloric acid solution, a pH4.0 phosphate buffer (6.80 g of potassium dihydrogen phosphate is taken and dissolved in water to 1000mL, and the pH value is adjusted to 4.0 by phosphoric acid or sodium hydroxide) and a pH6.8 phosphate buffer (6.80 g of potassium dihydrogen phosphate and 0.90g of sodium hydroxide are taken and dissolved in water to 1000mL, the pH value is adjusted to 6.8), 1000mL of water is taken as a dissolution medium, the rotating speed is 100 revolutions per minute, operating according to the method, taking an appropriate amount of the solution at a specified time point, filtering, precisely taking an appropriate amount of a subsequent filtrate, quantitatively diluting the subsequent filtrate with the dissolution medium to prepare a solution containing about 16 mu g of the active drug in each 1mL, and measuring absorbance at a wavelength of 250nm according to an ultraviolet-visible spectrophotometry according to the first method of the general rule of the national regulation of "Chinese pharmacopoeia" 2015 edition; taking another appropriate amount of active drug reference substance, precisely weighing, adding dissolution medium to dissolve and quantitatively diluting to obtain solution containing 16 μ g per 1ml, measuring by the same method, and calculating dissolution amount of each capsule in different dissolution media.
The method according to any one of the embodiments of the second aspect of the present invention, wherein the diluent in the second release phase portion is selected from the group consisting of: microcrystalline cellulose, starch, dextrin, lactose, dibasic calcium phosphate, and combinations thereof.
The process according to any embodiment of the second aspect of the present invention, wherein the weight of the diluent in the second release phase part is 30 to 80 parts by weight, for example 30 to 60 parts by weight, per 50 parts by weight of the active drug.
The method according to any one of the embodiments of the second aspect of the present invention, wherein the disintegrant in the first release phase portion is selected from the group consisting of: crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and combinations thereof.
The process according to any embodiment of the second aspect of the present invention, wherein the weight of the disintegrant in the second release phase fraction is 5 to 30 parts by weight, such as 10 to 20 parts by weight, per 50 parts by weight of active drug.
The method according to any one of the embodiments of the second aspect of the present invention, wherein the binder in the second release phase part is selected from the group consisting of: povidone, methylcellulose, ethylcellulose, carboxymethylcellulose, starch slurry, hypromellose, gelatin, polyethylene glycol, sodium alginate, water, ethanol, and combinations thereof. In one embodiment, the binder is selected from the group consisting of povidone, starch slurry, hypromellose, water, and combinations thereof. In one embodiment, the binder is selected from povidone, hypromellose, which is used in water formulated into binder solutions (such binder solutions typically used in the art have a concentration of typically 3-8%).
The method according to any embodiment of the second aspect of the present invention, wherein the binder is present in the second release phase fraction in an amount of 2 to 10 parts by weight, such as 3 to 8 parts by weight, per 50 parts by weight of active drug.
The method according to any of the embodiments of the second aspect of the present invention, wherein the coating layer of the second release phase part is a coating layer that is insoluble in the gastric acid environment. For example, the coating material used for the coating layer is a gastric-soluble type coating material. Examples of typical coating materials are e.g. cellulose acetate phthalate, hypromellose phthalate (HPMCP), polyvinyl alcohol phthalate (PVAP), Eudragit L, Eudragit S, acrylic resin I, acrylic resin II, acrylic resin IV, methacrylic acid copolymers, etc.
The process according to any embodiment of the second aspect of the present invention, wherein the weight of the coating layer in the second release phase fraction is 20 to 50 parts by weight, such as 20 to 40 parts by weight, per 50 parts by weight of the active drug.
The process according to any embodiment of the second aspect of the present invention, wherein the pellets of the second release phase fraction have an average diameter of 0.2 to 2mm, such as 0.5 to 1.5mm, such as 0.5 to 1.2mm, such as 0.5 to 0.8 mm.
The process according to any of the embodiments of the second aspect of the present invention, wherein the pellets of the second release phase fraction are taken in appropriate amounts at2 hours, 3 hours, 4 hours respectively upon dissolution in four dissolution media as determined by dissolution method a, the amount of dissolution at that time point in each dissolution media being determined, wherein:
the dissolution amount in two dissolution media of pH1.2 and pH4.0 at 4 hr is less than 10% of the main drug content in the pellet;
the dissolution amount in two dissolution media of pH6.8 and water at2 hours is less than 15% of the content of the main drug in the pellet;
the dissolution amount in two dissolution media of pH6.8 and water at 3 hours is more than 80% of the content of the main drug in the pellet.
According to the method of any embodiment of the second aspect of the present invention, the amount of the pharmaceutical composition eluted at the time point in each of the four dissolution media is determined by taking appropriate amounts of the solutions at 0.5 hour, 2 hours, 3 hours, and 4 hours, respectively, upon dissolution in the dissolution media as measured by dissolution assay method a, wherein:
the amount eluted at 0.5 hours in both dissolution media pH1.2 and pH4.0 is 90-120% (e.g. 90-110%) of the amount of drug in the first release phase portion of the pharmaceutical composition;
the amount eluted at 4 hours in both dissolution media pH1.2 and pH4.0 is 100-140% (e.g., 100-125%) of the amount of drug in the first release phase portion of the pharmaceutical composition;
the amount eluted at2 hours in both dissolution media pH6.8 and water is 100-140% (e.g. 100-130%) of the amount of drug in the first release phase portion of the pharmaceutical composition;
the amount of the extract in the two dissolution media of pH6.8 and water at 3 hr is more than 85% (such as more than 90%) of the amount of the Chinese medicinal materials in the pharmaceutical composition.
According to any of the embodiments of any of the aspects of the invention, wherein the pellets of the first release phase portion and the pellets of the second release phase portion of the pharmaceutical composition are each independently prepared according to a process comprising the steps of:
(1) adding the diluent and the disintegrant into the active medicine, uniformly mixing and crushing;
(2) preparing an adhesive solution with the concentration of 3-5% by using water, and preparing a soft material from the obtained material in the previous step;
(3) preparing pellets by extrusion-spheronization pelleting method or centrifugation-fluidization pelleting method, and drying to obtain pellet cores;
(4) coating the pellets of the second release phase fraction obtained in step (3), optionally with a coating of the pellets of the first release phase fraction;
(5) mixing the two pellets at a certain ratio, and filling into hollow capsule to obtain the pharmaceutical composition in the form of hard capsule preparation.
Any technical feature possessed by any one aspect of the invention or any embodiment of that aspect is equally applicable to any other embodiment or any embodiment of any other aspect, so long as they are not mutually inconsistent, although appropriate modifications to the respective features may be made as necessary when applicable to each other. Various aspects and features of the disclosure are described further below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure. Various aspects of the invention are described further below.
The English name of valsartan is valsartan, N-valeryl-N- [ [2'- (1H-tetrazole-5-yl) [1,1' -biphenyl]-4-yl]Methyl radical]-L-valine of formula: c24H29N5O3Molecular weight: 435.52, which is a white crystal or white, off-white powder; it has hygroscopic property. It is very soluble in ethanol, soluble in methanol, slightly soluble in ethyl acetate, and almost insoluble in water. Valsartan is a non-peptide, orally active angiotensin ii (AT) receptor antagonist. It is highly selective for the type i receptor (AT1) and competitively antagonizes without any agonistic effect. It also inhibits the release of aldosterone by adrenal cells mediated by the AT1 receptor, but has no inhibitory effect on potassium-induced release of valsartan, which also suggests a selective effect of valsartan on the AT1 receptor. The in vivo tests of various hypertension animal models show that the valsartan has good blood pressure reducing effect and has no obvious influence on the cardiac contraction function and the heart rate. It has no blood pressure lowering effect on animal with normal blood pressure. The oral preparation can be absorbed quickly, and the bioavailability is 23%. The binding rate of the protein to plasma protein is 94-97%. About 70% of the feces are excreted, and 30% of the feces are excreted from the kidney, all of which are in the original shape. t 1/2. beta. was about 9 hours. The curative effect is not affected when the medicine is taken with food. After the patient with hypertension takes the medicine once, the blood pressure begins to decrease within 2 hours, and the maximum blood pressure reducing effect is achieved after 4-6 hours. The hypotensive effect can last for 24 hours.The blood pressure reduction reaches the maximum effect 2-4 weeks after continuous medication. Can be used with hydrochlorothiazide, and has effect in lowering blood pressure. Valsartan is a non-precursor drug and has direct pharmacological activity without undergoing biotransformation by the liver. The oral administration has quick absorption, the absorption is influenced by eating, the bioavailability is 25 percent, and the binding rate with plasma protein is 95 percent. The medicine has quick effect and strong effect, the blood concentration reaches the peak value after 2 hours after the medicine is taken orally, and the effect lasts for more than 24 hours. The half-life period is 5-9 h, and the blood is discharged through biliary tract (70%) and kidney (30%). The valsartan is used for resisting hypertension and mild and moderate essential hypertension, and is particularly suitable for secondary hypertension caused by kidney damage. In general, valsartan is an angiotensin II receptor antagonist antihypertensive drug, and the drug has the effects of blocking angiotensin II type I (AT1) receptors, increasing angiotensin II plasma level, stimulating unblocked AT2 receptors and countering AT1 receptors, thereby achieving the effects of dilating blood vessels and reducing blood pressure. In the united states, valsartan is a drug used to treat hypertension, congestive heart failure, post-myocardial infarction. Valsartan, a product developed by Ciba-Geigy, Switzerland, acquired relative patent rights in the United states and Europe in 1995 and 1996, was first marketed in Germany in 7 months in 1996, and thereafter in Europe, the United states, Japan. Ciba-Geigy incorporated Nowa with Shande Shi in 1996. The valsartan has the characteristics of lasting and stable blood pressure reducing effect and small toxic and side effects.
Amlodipine, the english name Amlodipine, 6-methyl-2- (2-aminoethoxy) methyl-4- (2-chlorophenyl) -1, 4-dihydro-3, 5-pyridinedicarboxylic acid methylethyl ester, molecular formula: C20H25ClN2O5, molecular weight: 408.88. amlodipine is a nifedipine calcium antagonist. The effect of inhibiting calcium-induced aortic contraction is 2 times that of nifedipine. It is characterized by slow speed of binding and dissociation with receptors, so that the action of the drug is delayed and sustained for a long time. The selective effect on vascular smooth muscle is greater than that of nifedipine. It can increase cardiac output and coronary flow, increase myocardial oxygen supply, reduce oxygen consumption, and improve exercise ability for patients with myocardial ischemia. In addition, the product can activate LDL receptor, reduce accumulation of fat in artery wall and inhibit collagen synthesis, thus having anti-arteriosclerosis effect. The product has certain protective effect on kidney. The preparation comprises amlodipine besylate tablets, amlodipine mesylate tablets, levoamlodipine maleate tablets and the like. Amlodipine is suitable for treating mild and moderate hypertension, and has the curative effect similar to that of atenolol, captopril, diltiazem, nadolol, etc. Compared with verapamil, the antihypertensive drug has more continuous and stable antihypertensive effect and is used as a second-line drug for treating hypertension. The product can also be used for treating chronic stable angina (including patients with poor treatment effect on nitrate or beta-receptor blocking drugs), and can remarkably reduce angina attack frequency and prolong exercise time of patients. Amlodipine is clinically used for hypertension, and can be used alone or combined with other antihypertensive drugs; can also be used for chronic stable angina pectoris or vasospastic angina pectoris, and can be used alone or in combination with other antianginal drugs, such as nitrates and/or beta-blockers.
The method for treating hypertension by using the time release medicine and the pharmaceutical composition provided by the method have the excellent technical effects as described in the text.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible.
In the following specific examples section, the preparation of the formulation compositions is carried out, if not mentioned otherwise, in a dose of 100000 units of formulation or at least 5kg of material.
In the present invention, the pellets of the first release phase portion are rapidly released in vivo, and thus the pellets of this portion may also be referred to as immediate release pellets or immediate release pellets; for the same reason, the pellets of the second release phase fraction need to be delayed in vivo, and therefore the pellets of this fraction may also be referred to as delayed release pellets or extended release pellets or also as sustained release pellets or sustained release pellets.
Example 1 preparation of immediate Release pellets
The prescription proportion is as follows:
valsartan 30 parts by weight
Starch (diluent) 45 weight portions
15 parts by weight of sodium carboxymethyl starch (disintegrant)
5 parts of povidone (adhesive).
Preparation of pellets:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a 4% solution of the adhesive by using water as an adhesive solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. The pellets are moved into a drying room for drying, the drying condition is 30 +/-2 ℃, the drying time is 12 hours, and the dried pellets can be used as the quick-release pellets of the invention.
Example 2 preparation of immediate Release pellets
The prescription proportion is as follows:
valsartan 30 parts by weight
Dextrin (diluent) 30 weight portions
15 parts by weight of croscarmellose sodium (disintegrant)
And 8 parts of hydroxypropyl methylcellulose (adhesive).
Preparation of pellets:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a binder into a solution with the concentration of 8% by using water to serve as a binder solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. The pellets are moved into a drying room for drying, the drying condition is 30 +/-2 ℃, the drying time is 12 hours, and the dried pellets can be used as the quick-release pellets of the invention.
Example 3 preparation of immediate Release pellets
The prescription proportion is as follows:
valsartan 30 parts by weight
60 parts by weight of microcrystalline cellulose (diluent)
12 parts by weight of low-substituted hydroxypropyl cellulose (disintegrant)
And 3 parts of povidone (adhesive).
Preparation of pellets:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a binder into a solution with the concentration of 3% by using water to serve as a binder solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. The pellets are moved into a drying room for drying, the drying condition is 30 +/-2 ℃, the drying time is 12 hours, and the dried pellets can be used as the quick-release pellets of the invention.
Example 4 preparation of immediate Release pellets
The prescription proportion is as follows:
valsartan 30 parts by weight
Lactose (diluent) 80 parts by weight
20 parts by weight of crospovidone (disintegrant)
Povidone (adhesive) 4 parts by weight.
Preparation of pellets:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a 5% solution of the adhesive by using water as an adhesive solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. The pellets are moved into a drying room for drying, the drying condition is 30 +/-2 ℃, the drying time is 12 hours, and the dried pellets can be used as the quick-release pellets of the invention.
Example 5 preparation of immediate Release pellets
The prescription proportion is as follows:
valsartan 30 parts by weight
40 parts of starch/calcium hydrogen phosphate (1/2, diluent)
10 parts by weight of sodium carboxymethyl starch/croscarmellose sodium (1/1, disintegrant)
And 6 parts of povidone (adhesive).
Preparation of pellets:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a 5% solution of the adhesive by using water as an adhesive solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. The pellets are moved into a drying room for drying, the drying condition is 30 +/-2 ℃, the drying time is 12 hours, and the dried pellets can be used as the quick-release pellets of the invention.
Example 6 preparation of immediate Release pellets
The prescription proportion is as follows:
valsartan 30 parts by weight
50 parts by weight of microcrystalline cellulose/starch (1/2, diluent)
15 parts by weight of sodium carboxymethyl starch (disintegrant)
7 parts of hydroxypropyl methylcellulose (adhesive).
Preparation of pellets:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a 5% solution of the adhesive by using water as an adhesive solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. The pellets are moved into a drying room for drying, the drying condition is 30 +/-2 ℃, the drying time is 12 hours, and the dried pellets can be used as the quick-release pellets of the invention.
Example 7 preparation of immediate Release pellets
The prescription proportion is as follows:
valsartan 30 parts by weight
Dextrin (diluent) 45 weight portions
16 parts by weight of croscarmellose sodium (disintegrant)
4 parts of hydroxypropyl methylcellulose (adhesive).
Preparation of pellets:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a 5% solution of the adhesive by using water as an adhesive solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. The pellets are moved into a drying room for drying, the drying condition is 30 +/-2 ℃, the drying time is 12 hours, and the dried pellets can be used as the quick-release pellets of the invention.
Example 8 preparation of immediate Release pellets
The prescription proportion is as follows:
valsartan 30 parts by weight
40 parts by weight of starch/lactose (1/2, diluent)
5 parts by weight of croscarmellose sodium/crospovidone (2/1, disintegrant)
Povidone (adhesive) 4 parts by weight.
Preparation of pellets:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a 5% solution of the adhesive by using water as an adhesive solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. The pellets are moved into a drying room for drying, the drying condition is 30 +/-2 ℃, the drying time is 12 hours, and the dried pellets can be used as the quick-release pellets of the invention.
Example 9 preparation of immediate Release pellets
The prescription proportion is as follows:
valsartan 30 parts by weight
Dextrin/starch (2/1, diluent) 50 parts by weight
10 parts by weight of sodium carboxymethyl starch (disintegrant)
5 parts of povidone (adhesive).
Preparation of pellets:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a 5% solution of the adhesive by using water as an adhesive solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. The pellets are moved into a drying room for drying, the drying condition is 30 +/-2 ℃, the drying time is 12 hours, and the dried pellets can be used as the quick-release pellets of the invention.
The dissolution amount of each of the immediate release pellets of examples 1 to 9 is larger than 80% of the content of the main drug in the pellets and is in the range of 88 to 95% in four dissolution media at 30min, measured by dissolution test method A.
Example 10: quick release pellet coating
The pellets of examples 1-3, 4-6 and 7-9 were coated with a commercially available hydroxypropyl methylcellulose based coating pre-mix powder, Eudragit E based coating pre-mix powder, hydroxypropyl cellulose based coating pre-mix powder (all available from calcon and formulated as coating solutions according to the product specifications) respectively, using a weight of 20 parts, 15 parts and 25 parts per 30 parts by weight of active drug per each group of pellets to give 9 coated pellets. When the dissolution rate determination method A is used for determining the dissolution rate of the coated pellets, the dissolution rate of the coated pellets in four dissolution media is more than 80 percent of the content of the main drug in the pellets and is in the range of 87-95 percent at 30min, and the dissolution rates of the pellets obtained in the same example before and after coating are not obviously different (the difference of the dissolution rates is less than 1 percent). In addition, the average diameter of the coated immediate release pellets is in the range of 0.5 to 0.8 mm.
EXAMPLE 11 preparation of core for extended Release pellets
The prescription proportion is as follows:
50 parts by weight of valsartan
Dextrin (diluent) 45 weight portions
15 parts by weight of sodium carboxymethyl starch (disintegrant)
5 parts of povidone (adhesive).
Preparing a pill core:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a 4% solution of the adhesive by using water as an adhesive solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. Transferring into drying chamber, drying at 30 + -2 deg.C for 12 hr, drying to obtain pill core, and coating.
EXAMPLE 12 preparation of core for extended Release pellets
The prescription proportion is as follows:
50 parts by weight of valsartan
Microcrystalline cellulose (diluent) 30 parts by weight
15 parts by weight of low-substituted hydroxypropyl cellulose (disintegrant)
And 8 parts of hydroxypropyl methylcellulose (adhesive).
Preparing a pill core:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a binder into a solution with the concentration of 8% by using water to serve as a binder solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. Transferring into drying chamber, drying at 30 + -2 deg.C for 12 hr, drying to obtain pill core, and coating.
EXAMPLE 13 preparation of core for extended Release pellets
The prescription proportion is as follows:
50 parts by weight of valsartan
60 parts of starch (diluent)
12 parts by weight of croscarmellose sodium (disintegrant)
And 3 parts of povidone (adhesive).
Preparing a pill core:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a binder into a solution with the concentration of 3% by using water to serve as a binder solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. Transferring into drying chamber, drying at 30 + -2 deg.C for 12 hr, drying to obtain pill core, and coating.
EXAMPLE 14 preparation of core for extended Release pellets
The prescription proportion is as follows:
50 parts by weight of valsartan
Lactose (diluent) 80 parts by weight
20 parts by weight of crospovidone/sodium carboxymethyl starch (1/1, disintegrant)
Povidone (adhesive) 4 parts by weight.
Preparing a pill core:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a 5% solution of the adhesive by using water as an adhesive solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. Transferring into drying chamber, drying at 30 + -2 deg.C for 12 hr, drying to obtain pill core, and coating.
EXAMPLE 15 preparation of core for extended Release pellets
The prescription proportion is as follows:
50 parts by weight of valsartan
40 parts of starch/calcium hydrogen phosphate (2/1, diluent)
10 parts by weight of sodium carboxymethyl starch/croscarmellose sodium (1/2, disintegrant)
And 6 parts of povidone (adhesive).
Preparing a pill core:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a 5% solution of the adhesive by using water as an adhesive solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. Transferring into drying chamber, drying at 30 + -2 deg.C for 12 hr, drying to obtain pill core, and coating.
Example 16 pellets with extended Release pelletsPreparation of the cores
The prescription proportion is as follows:
50 parts by weight of valsartan
Microcrystalline cellulose/lactose (2/1, diluent) 50 parts by weight
15 parts by weight of crospovidone (disintegrant)
7 parts of hydroxypropyl methylcellulose (adhesive).
Preparing a pill core:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a 5% solution of the adhesive by using water as an adhesive solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. Transferring into drying chamber, drying at 30 + -2 deg.C for 12 hr, drying to obtain pill core, and coating.
EXAMPLE 17 preparation of core for extended Release pellets
The prescription proportion is as follows:
50 parts by weight of valsartan
Lactose (diluent) 45 parts by weight
16 parts by weight of croscarmellose sodium (disintegrant)
4 parts of hydroxypropyl methylcellulose (adhesive).
Preparing a pill core:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a 5% solution of the adhesive by using water as an adhesive solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. Transferring into drying chamber, drying at 30 + -2 deg.C for 12 hr, drying to obtain pill core, and coating.
EXAMPLE 18 preparation of core for extended Release pellets
The prescription proportion is as follows:
50 parts by weight of valsartan
50 parts by weight of starch/lactose (2/1, diluent)
15 parts by weight of croscarmellose sodium/crospovidone (1/2, disintegrant)
Povidone (adhesive) 4 parts by weight.
Preparing a pill core:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a 4% solution of the adhesive by using water as an adhesive solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. Transferring into drying chamber, drying at 30 + -2 deg.C for 12 hr, drying to obtain pill core, and coating.
EXAMPLE 19 preparation of core for extended Release pellets
The prescription proportion is as follows:
50 parts by weight of valsartan
Dextrin/starch (2/1, diluent) 55 parts by weight
5 parts by weight of sodium carboxymethyl starch (disintegrant)
5 parts of povidone (adhesive).
Preparing a pill core:
(1) mixing the active medicine, the diluent and the disintegrating agent uniformly according to the proportion of the prescription, crushing the mixture together to pass through a 100-mesh sieve, and mixing the mixture uniformly;
(2) preparing a 5% solution of the adhesive by using water as an adhesive solution;
(3) preparing the mixed powder in the step (1) into a soft material by using a binder solution, preparing the pellets by adopting an extrusion-spheronization pill forming method, extruding the mixed wet material into strips at an extrusion speed of 10-40r/min, moving the strips into a spheronization device, cutting the extrudate at a rotating speed of 40-70Hz, and spheronizing the strips at a rotating speed of 30-50Hz for 10-20 minutes to prepare the pellets. Transferring into drying chamber, drying at 30 + -2 deg.C for 12 hr, drying to obtain pill core, and coating.
The pellet cores of examples 11 to 19 were dissolved out in four kinds of dissolution media at 30min in a range of 87 to 96% in each of which the amount of dissolution was more than 85% of the content of the main drug in the pellet, as measured by dissolution test method A.
Example 20: delayed release pellet coating
Nine pellets of examples 11 to 19 were coated with each other by using 9 kinds of commercially available cellulose acetate phthalate based coating pre-mixed powder, hypromellose phthalate based coating pre-mixed powder, polyvinyl alcohol phthalate based coating pre-mixed powder, Eudragit L based coating pre-mixed powder, Eudragit S based coating pre-mixed powder, acrylic resin I based coating pre-mixed powder, acrylic resin II based coating pre-mixed powder, acrylic resin IV based coating pre-mixed powder, methacrylic acid copolymer based coating pre-mixed powder (all available from kallikang corporation and formulated into coating solutions according to the product specifications), the coating layer was used in each pellet in the amounts of 20 parts by weight (examples 11-13), 15 parts by weight (examples 14-16), and 25 parts by weight (examples 17-19), respectively, per 50 parts by weight of the active drug, to give 9 coated pellets. The formulation of these coating materials, for example, methacrylic acid copolymer-based coating premix powders, is: 200 parts of methacrylic acid copolymer, 20 parts of triethyl citrate, 40 parts of talcum powder and 1740 parts of water for preparation when in use; for another example, the formula of the acrylic resin II-based coating premixed powder is as follows: 300 parts of acrylic resin II, 20 parts of hydroxypropyl methyl fiber, 50 parts of titanium dioxide, 75 parts of zein, 40 parts of polyethylene glycol and 15 parts of glycerol, and 500 parts of water is added for preparation when in use.
In the context of the present invention, the process conditions used when carrying out the various coating processes are: a Glatt fluidized bed coating machine is used, the airflow temperature is 55 ℃, the pellet temperature is 32 ℃, the atomization pressure is 0.25-0.30MPa, the guniting speed is 150mL/min, and the coating weight gain control is determined according to the prescription.
The coated pellets have an average diameter in the range of 0.5 to 0.8 mm.
The coated pellets were subjected to a dissolution test A, and when the pellets were dissolved in four dissolution media, appropriate amounts of the solutions were taken at1 hour, 2 hours, 3 hours, and 4 hours, respectively, to measure the amount of dissolution in each dissolution medium at that time point, and as a result: the dissolution amount in two dissolution media of pH1.2 and pH4.0 at 4 hours is less than 10% of the content of the main drug in the pellet and is in the range of 2-5%; the dissolution amount in two dissolution media of pH6.8 and water at1 hour reaches the range of 85-91% of the content of the main drug in the pellet; the dissolution amount in two dissolution media of pH6.8 and water at2 hours is more than 93 percent of the content of the main drug in the pellet.
This indicates that these pellets exhibited different release patterns before and after coating, with essentially no release at low pH, but a significant portion already released in neutral medium before 1 hour, which release pattern was not in compliance with the design requirements for controlling morning waking hypertension; although this release pattern is consistent with the release expectations of typical enteric formulations.
In addition, one of these coated delayed release pellets obtained in example 20 was mixed with any of the coated immediate release pellets obtained in example 10 (in an active ingredient ratio of 50: 30) and filled in empty capsules, each containing 80mg of the active ingredient. The pharmaceutical composition of capsules containing two kinds of pellets was measured by dissolution test method a, and when the composition was dissolved in four dissolution media, appropriate amounts of solutions were taken at 0.5 hour, 1 hour, 2 hours, 3 hours, and 4 hours, respectively, to measure the amount of dissolution in each dissolution medium at that time point, and as a result: the amount eluted at 0.5 hours in both dissolution media pH1.2 and pH4.0 is 90-120% (e.g. 90-110%) of the amount of drug in the first release phase portion of the pharmaceutical composition; the amount eluted at 4 hours in both dissolution media pH1.2 and pH4.0 is 100-140% (e.g., 100-125%) of the amount of drug in the first release phase portion of the pharmaceutical composition; the dissolution amount in two dissolution media of pH6.8 and water at1 hour reaches 91-95% of the content of the main drug in the capsule; the dissolution amount in two dissolution media of pH6.8 and water at2 hr is more than 96% of the content of the main drug in the capsule. These results indicate that it is difficult to achieve a drug release pattern with two release times before 1 and 5 hours after the two pellet combinations were taken around 9 nights.
Example 21: delayed release pellet coating
Nine pellets of examples 11 to 19 were subjected to delayed-release pellet coating in accordance with the procedure of example 20 above, except that 2% (percent by weight with respect to the weight of the coating material) of a coating aid was additionally added to the coating solution to obtain 9 kinds of coated pellets.
The coated pellets were subjected to a dissolution test A, and when the pellets were dissolved in four dissolution media, appropriate amounts of the solutions were taken at2 hours, 3 hours, and 4 hours, respectively, to measure the amount of dissolution in each dissolution medium at that time point, and as a result: the dissolution amount in two dissolution media of pH1.2 and pH4.0 at 4 hours is less than 10% of the content of the main drug in the pellet and is in the range of 3-6%; the dissolution amount in two dissolution media of pH6.8 and water at2 hours is less than 15 percent of the content of the main drug in the pellet and is in the range of 6 to 11 percent; the dissolution amount in two dissolution media of pH6.8 and water at 3 hours is more than 80 percent of the content of the main drug in the pellet, and the dissolution amounts are both in the range of 88 to 94 percent. These results show thatDelayed release coated pellet obtained in example 21The delayed release pattern in intestinal fluid environment meets the design requirements for controlling morning blood pressure, and the delayed release pattern in intestinal fluid environment can meet the design requirements of controlling morning blood pressure.
Example 22: preparation of hard capsules with biphasic Release Properties
The delayed release coated pellets (pellets as the second release phase portion) obtained in example 21 above were mixed with the various immediate release coated pellets (pellets as the first release phase portion) obtained in example 10 in the ratio of 7:3, 7:4, 7:5, 5:3, 5:4, 7:5, respectively, by weight of the active ingredient, and the resulting mixed pellets were filled into hard capsules each containing 80mg of valsartan, to obtain hard capsules having a biphasic release property. These hard capsules were measured by the dissolution test method A, and when they were dissolved in four dissolution media, appropriate amounts of the solutions were taken at 0.5 hour, 2 hours, 3 hours, and 4 hours, respectively, to measure the amount of dissolution in each dissolution medium at that time point, and as a result:
the dissolution amount of all capsules in two dissolution media of pH1.2 and pH4.0 at 0.5 hour is 93-109% of the drug amount of the first release phase in the hard capsule drug composition; the dissolution amount in two dissolution media of pH1.2 and pH4.0 at 4 hr is 103-121% of the medicine amount of the first release phase part in the hard capsule pharmaceutical composition; the dissolution amount in two dissolution media of pH6.8 and water at2 hours is 107-129% of the medicine amount of the first release phase part in the hard capsule medicine composition; the dissolution amount in two dissolution media of pH6.8 and water at 3 hours is more than 85% (both are in the range of 94-97%) of the traditional Chinese medicine amount of the hard capsule pharmaceutical composition.
The above results show that the resulting sustained release coated pellets and the resulting dual phase release hard capsule formulation exhibit the dual phase release performance as in the present invention typically spaced about 5 hours apart only when a trace amount of coating aid is added to the second release phase partial coating solution.
Example 23: preparation of hard capsules with biphasic Release Properties
With reference to the prescription and method of example 10 above, respectively, the active ingredient was changed to amlodipine besylate to give immediate release pellets having the properties of the first release phase portion; the active ingredient was changed to amlodipine besylate to give extended release pellets having the properties of the second release phase portion with reference to the formulation and method of example 21 above, respectively. The two types of pellets were tested according to dissolution test a and the results showed that their release patterns were substantially identical to the pellets described in example 10 and example 21, respectively. The above two amlodipine besylate pellets were used to prepare hard capsules having biphasic release property in the same manner as in example 22, each capsule containing 5mg of amlodipine besylate, to obtain hard capsules having biphasic release property. These hard capsules were tested according to dissolution test A and showed a release pattern substantially identical to that of the hard capsules described in example 22, namely: the drug of the first release phase part is mainly released within 4 hours in an acidic medium, the drug of the first release phase part is mainly released within 2 hours in a neutral medium, and the drug of the first release phase part and the drug of the second release phase part are basically and completely released at 3 hours in the neutral medium.
Example 24: preparation of hard capsules with biphasic Release Properties
With reference to the prescription and method of example 10 above, respectively, the active ingredient was changed to captopril, resulting in immediate release pellets having the properties of a first release phase portion; the active ingredient was changed to captopril to give extended release pellets having the properties of the second release phase portion, with reference to the formulation and method of example 21 above, respectively. The two types of pellets were tested according to dissolution test a and the results showed that their release patterns were substantially identical to the pellets described in example 10 and example 21, respectively. Hard capsules having biphasic release properties were prepared from the above two captopril pellets in the same manner as in example 22, each capsule containing 50mg of captopril to give hard capsules having biphasic release properties. These hard capsules were tested according to dissolution test A and showed a release pattern substantially identical to that of the hard capsules described in example 22, namely: the drug of the first release phase part is mainly released within 4 hours in an acidic medium, the drug of the first release phase part is mainly released within 2 hours in a neutral medium, and the drug of the first release phase part and the drug of the second release phase part are basically and completely released at 3 hours in the neutral medium.

Claims (19)

1. A pharmaceutical composition for timed release drug therapy of hypertension, comprising a first release phase part and a second release phase part in the form of pellets, respectively; wherein the pellets of the first release phase portion comprise: active drug, diluent, disintegrant, binder and optionally a coating layer, the pellets of the second release phase portion comprising: active drug, diluent, disintegrating agent, adhesive and coating layer for regulating drug release;
wherein:
the active agent is a hypotensive agent;
the active drug in the first release phase part accounts for 30-50% of the total amount of the active drug in the pharmaceutical composition, and the active drug in the second release phase part accounts for 50-70% of the total amount of the active drug in the pharmaceutical composition;
the diluent in the first release phase portion is selected from: microcrystalline cellulose, starch, dextrin, lactose, dibasic calcium phosphate, and combinations thereof;
the disintegrant in the first release phase portion is selected from: crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and combinations thereof;
the binder in the first release phase portion is selected from: povidone, methylcellulose, ethylcellulose, carboxymethylcellulose, starch slurry, hypromellose, gelatin, polyethylene glycol, sodium alginate, water, ethanol, and combinations thereof;
the coating layer of the first release phase part is a coating layer which can be dissolved in the gastric acid environment;
the pellets of the first release phase portion have an average diameter of 0.2 to 2 mm; and
the pellets of the first release phase fraction were tested in the following dissolution test method a, which at 30min gave dissolution in four dissolution media of more than 80% of the content of the main drug in the pellets, the operation of which was as follows: taking a proper amount of pellets which are equivalent to 50mg of active medicine, filling the pellets into hollow capsules, respectively using 1000ml of hydrochloric acid solution with pH1.2, phosphate buffer solution with pH4.0, phosphate buffer solution with pH6.8 and water as dissolution media according to the first method of 0931 of the general rule of the four departments of the 2015 edition of Chinese pharmacopoeia, operating according to the method at the rotating speed of 100 r/min, taking a proper amount of solution at a specified time point, filtering, taking a proper amount of subsequent filtrate precisely, quantitatively diluting the subsequent filtrate with the dissolution media to prepare a solution containing 16 mu g of active medicine in each 1ml, and measuring the absorbance at the wavelength of 250nm by an ultraviolet-visible spectrophotometry; taking another appropriate amount of active drug reference substance, precisely weighing, adding dissolution medium to dissolve and quantitatively diluting to obtain solution containing 16 μ g per 1ml, measuring by the same method, and calculating dissolution amount of each capsule in different dissolution media; the preparation method of the pH4.0 phosphate buffer solution comprises the following steps: taking 6.80g of monopotassium phosphate, adding water to dissolve the monopotassium phosphate into 1000mL of monopotassium phosphate, and adjusting the pH value to 4.0 by using phosphoric acid or sodium hydroxide, wherein the preparation method of a phosphate buffer solution with the pH value of 6.8 comprises the following steps: dissolving 6.80g of monopotassium phosphate and 0.90g of sodium hydroxide in water to 1000mL, and adjusting the pH value to 6.8;
the diluent in the second release phase portion is selected from: microcrystalline cellulose, starch, dextrin, lactose, dibasic calcium phosphate, and combinations thereof;
the disintegrant in the second release phase portion is selected from: crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and combinations thereof;
the binder in the second release phase portion is selected from: povidone, methylcellulose, ethylcellulose, carboxymethylcellulose, starch slurry, hypromellose, gelatin, polyethylene glycol, sodium alginate, water, ethanol, and combinations thereof;
the coating layer of the second release phase part is a coating layer which cannot be dissolved in the gastric acid environment, and the coating material of the coating layer is selected from the following group: cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol ester phthalate, Eudragit L, Eudragit S, acrylic resin I, acrylic resin II, acrylic resin IV and methacrylic acid copolymer; the coating layer of the second release phase part also contains coating auxiliary agent liquid paraffin, and when the pellets of the second release phase part are coated, the coating auxiliary agent liquid paraffin added into the coating liquid is 2 percent of the weight of the coating material;
the pellets of the second release phase portion have an average diameter of 0.2 to 2 mm;
the pellets of the second release phase fraction were measured according to dissolution method a, and the amount of dissolution at that time point in each dissolution medium was determined by taking appropriate amounts of the solution at2 hours, 3 hours, 4 hours respectively upon dissolution in four dissolution media, wherein:
the dissolution amount in two dissolution media of pH1.2 and pH4.0 at 4 hr is less than 10% of the main drug content in the pellet;
the dissolution amount in two dissolution media of pH6.8 and water at2 hours is less than 15% of the content of the main drug in the pellet;
the dissolution amount in two dissolution media of pH6.8 and water at 3 hours is more than 80% of the content of the main drug in the pellet.
2. The pharmaceutical composition according to claim 1, wherein the active drug is selected from the group consisting of: valsartan, amlodipine and pharmaceutically acceptable salts thereof, captopril.
3. The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable salt of amlodipine is a maleate, benzenesulfonate, aspartate, or methanesulfonate salt of amlodipine.
4. The pharmaceutical composition according to claim 1, wherein the diluent is present in the first release phase part in an amount of 30 to 80 parts by weight per 30 parts by weight of the active pharmaceutical agent.
5. The pharmaceutical composition according to claim 1, wherein the disintegrant is present in the first release phase part in an amount of 5 to 30 parts by weight per 30 parts by weight of the active drug.
6. The pharmaceutical composition according to claim 1, wherein the binder is present in the first release phase part in an amount of 2 to 10 parts by weight per 30 parts by weight of the active agent.
7. The pharmaceutical composition according to claim 1, wherein the coating material of the coating layer of the first release phase part is selected from the group consisting of: eudragit E, hydroxypropyl methylcellulose, hydroxypropyl cellulose.
8. The pharmaceutical composition according to claim 1, wherein the weight of the coating layer in the first release phase part is 10 to 30 parts by weight per 30 parts by weight of the active drug.
9. The pharmaceutical composition according to claim 1, the pellets of the first release phase fraction having an average diameter of 0.5 to 1.2 mm.
10. The pharmaceutical composition according to claim 1, wherein the diluent is present in the second release phase part in an amount of 30 to 80 parts by weight per 50 parts by weight of the active pharmaceutical agent.
11. The pharmaceutical composition according to claim 1, wherein the disintegrant is present in the second release phase part in an amount of 5 to 30 parts by weight per 50 parts by weight of the active drug.
12. The pharmaceutical composition according to claim 1, wherein the binder is present in the second release phase part in an amount of 2 to 10 parts by weight per 50 parts by weight of the active agent.
13. The pharmaceutical composition according to claim 1, wherein the weight of the coating layer in the second release phase part is 20 to 50 parts by weight per 50 parts by weight of the active drug.
14. The pharmaceutical composition according to claim 1, wherein the pellets of the second release phase fraction have an average diameter of 0.5 to 1.2 mm.
15. The pharmaceutical composition according to claim 1, wherein the amount of dissolution in each dissolution medium at that time point is determined by taking appropriate amounts of solution at 0.5 hour, 2 hours, 3 hours, 4 hours, respectively, upon dissolution in four dissolution media, as determined by dissolution assay a, wherein:
the dissolution amount in two dissolution media of pH1.2 and pH4.0 at 0.5 hr is 90-120% of the drug amount in the first release phase part of the pharmaceutical composition;
the dissolution amount in two dissolution media of pH1.2 and pH4.0 at 4 hr is 100-140% of the drug amount in the first release phase part of the pharmaceutical composition;
the dissolution amount in two dissolution media of pH6.8 and water at2 hours is 100-140% of the drug amount of the first release phase part in the drug composition;
the dissolution amount in two dissolution media of pH6.8 and water at 3 hr is more than 85% of the traditional Chinese medicine amount in the pharmaceutical composition.
16. The pharmaceutical composition according to claim 1, wherein the amount of dissolution in each dissolution medium at that time point is determined by taking appropriate amounts of solution at 0.5 hour, 2 hours, 3 hours, 4 hours, respectively, upon dissolution in four dissolution media, as determined by dissolution assay a, wherein:
the dissolution amount in two dissolution media of pH1.2 and pH4.0 at 0.5 hr is 90-110% of the drug amount in the first release phase part of the pharmaceutical composition;
the dissolution amount in two dissolution media of pH1.2 and pH4.0 at 4 hr is 100-125% of the drug amount in the first release phase part of the pharmaceutical composition;
the dissolution amount in two dissolution media of pH6.8 and water at2 hours is 100-130% of the drug amount of the first release phase part in the drug composition;
the dissolution amount in two dissolution media of pH6.8 and water at 3 hr is more than 90% of the amount of the Chinese medicinal materials in the pharmaceutical composition.
17. The pharmaceutical composition according to any of claims 1 to 16, wherein the pellets of the first release phase portion and the pellets of the second release phase portion are each independently prepared according to a process comprising the steps of:
(1) adding the diluent and the disintegrant into the active medicine, uniformly mixing and crushing;
(2) preparing an adhesive solution with the concentration of 3-5% by using water, and preparing a soft material from the obtained material in the previous step;
(3) preparing pellets by extrusion-spheronization pelleting method or centrifugation-fluidization pelleting method, and drying to obtain pellet cores;
(4) coating the pellets of the second release phase fraction obtained in step (3), optionally with a coating of the pellets of the first release phase fraction;
(5) mixing the two pellets at a certain ratio, and filling into hollow capsule to obtain the pharmaceutical composition in the form of hard capsule preparation.
18. Use of a pharmaceutical composition according to any one of claims 1 to 17 in the manufacture of a medicament for the timed release of a drug for the treatment of hypertension.
19. The use according to claim 18, wherein said timed release medicament for the treatment of hypertension is to administer to a hypertensive patient in need thereof a therapeutically effective amount of said pharmaceutical composition at night before bedtime.
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