CN102247598A - Oil-soluble drug composition - Google Patents
Oil-soluble drug composition Download PDFInfo
- Publication number
- CN102247598A CN102247598A CN2011101577525A CN201110157752A CN102247598A CN 102247598 A CN102247598 A CN 102247598A CN 2011101577525 A CN2011101577525 A CN 2011101577525A CN 201110157752 A CN201110157752 A CN 201110157752A CN 102247598 A CN102247598 A CN 102247598A
- Authority
- CN
- China
- Prior art keywords
- oil
- soluble medicine
- solubilizing agent
- capsule
- fenofibrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses an oil-soluble drug composition, belonging to the field of chemical drug preparation. The oil-soluble drug composition comprises an internal material and an external packaging material, wherein the internal material is oil-soluble liquid prepared from an oil-soluble drug and auxiliary ingredients; the auxiliary ingredients are a non-polar solvent and a solubilizing agent; the non-polar solvent is vegetable oil, animal oil or polyoxyethylene-40-hydrogenated castor oil; and the solubilizing agent is isopropyl myristate and/or ethyl oleate, tween, polyethylene glycol 400 and polyethylene glycol 600. The composition is in a dosage form of soft capsules, which are prepared from the oil-soluble drug used as a primary drug matched with the solubilizing agent for improving the drug dissolution and have high bioavailability.
Description
Technical field
The present invention relates to field of medicaments, particularly, relate to a kind of oil-soluble medicine combination of compositions thing and preparation method thereof.
Background technology
Fenofibrate (another name Fenofibrate, Fenofibrate, Lipilfen, English name Fenofibrate, chemical formula C
20H
21ClO
4), be white or off-white color crystalline powder; Odorless, tasteless.Very easily dissolving is easily molten in acetone or ether in chloroform, and is molten in the ethanol part omitted, almost insoluble in water.Fusing point is 78～82 ℃.Effect through esterase is metabolized to fenofibrate acid rapidly and plays effect for reducing blood fat in vivo, has tangible reduction serum cholesterol, the effect of triglyceride and high density lipoprotein increasing.Effect with obvious reduction plasma TG and TC is applicable to treatment hypertriglyceridemia and hypercholesterolemia, few side effects.
Domestic existing fenofibrate compositions mainly comprises at present: tablet, capsule, soft gelatin capsule, chewable tablet, dispersible tablet, slow releasing capsule, micro powder granule, slow-release pill etc.But existing dosage form dissolution is low, and bioavailability is not very high.
The oily soluble drug compositions that the present invention relates to is mainly hormones, or vitamins etc. mainly shows as at vegetable oil, or dissolves in the fatty oil, slightly molten, slightly soluble, very slightly soluble medicine.
As everyone knows, mostly hormone medicine water insoluble or pure in, route of administration is relatively limited to, main still administrated by injection, oral administration exists and absorbs not exclusively at present, and side effect is bigger, and is bigger to hepatotoxicity.
Therefore need improve its existing peroral dosage form.
Summary of the invention
The objective of the invention is the defective low at dissolution in the oral drugs in the prior art, that bioavailability is low, propose a kind of novel oil-soluble medicine compositions.
This oil-soluble medicine preparation of compositions method also is provided simultaneously.
The oil-soluble medicine compositions comprises content and outer covering material, the oil solution of described content for being made by oil-soluble medicine and adjuvant; Described adjuvant is non-polar solven and solubilizing agent, and described non-polar solven is vegetable oil, animal oil or polyoxyl 40 hydrogenated castor oil; Described solubilizing agent is isopropyl myristate and/or ethyl oleate, tween, PEG400, Macrogol 600.
Described vegetable oil is one or more in Oleum Arachidis hypogaeae semen, soybean oil, Oleum Brassicae campestris, Semen Maydis oil, olive oil, Oleum Helianthi, Oleum sesami, Semen Lini oil, Oleum Gossypii semen, Testa oryzae oil, Oleum Cocois, camellia seed oil, low erucic acid rapeseed oil, Fructus Zanthoxyli oil, the Fructus Capsici wet goods, and described animal oil is one or more in Adeps Sus domestica, Adeps Bovis seu Bubali, Adeps Caprae seu ovis, chicken oil, the duck oil.
Described solubilizing agent is isopropyl myristate and/or ethyl oleate, tween, PEG400, Macrogol 600.
In per 1000 preparation compositions, contain oil-soluble medicine 2-70g, solubilizing agent 1-210g, vegetable oil 400～1000g.
Described oil-soluble medicine is fenofibrate, probucol, undecylenic acid, testosterone undecanoate, diethylstilbestrol, hydroxyprogesterone caproate, Testosterone Propionate, methyltestosterone, nandrolone phenylpropionate, estradiol benzoate, Fluphenazine or vitamin D3.
In per 1000 preparation compositions, described oil-soluble medicine 5g, solubilizing agent are one or more 15g in isopropyl myristate, ethyl oleate, tween, PEG400, the Macrogol 600, vegetable oil 500-900g.
In per 1000 preparation compositions, described oil-soluble medicine 25g, solubilizing agent are one or more 20g in isopropyl myristate, ethyl oleate, tween, PEG400, the Macrogol 600, vegetable oil 500-900g.
In per 1000 preparation compositions, one or more 150g in described oil-soluble medicine 50g, solubilizing agent isopropyl myristate and/or ethyl oleate, tween, PEG400, the Macrogol 600, vegetable oil 500-900g.
Its preparation formulation is soft capsule, liquid capsule, hard capsule or drop pill.
Described outer covering material contains gelatin, or gelatin and propylene glycol or gelatin and glycerol.
Its preparation formulation is that capsule wraps enteric coating outward again.
Described oil-soluble medicine preparation of compositions method, comprise: take by weighing each component of content in proportion, its mixing is stirred evenly, obtain oil solution, oil solution is got the filling of an amount of usefulness revolving die formula soft gelatin capsule maker in capsule, with enteric coating in soft capsule or liquid capsule or hard capsule or the drop pill outsourcing.
Described mixing stirs evenly under temperature 10-65 ℃ condition and stirs, and adopts ultrasonic assist in dissolving when described mixing stirs evenly.
The content assaying method of above-mentioned oil-soluble medicine (fenofibrate) compositions is a filler with octadecylsilane chemically bonded silica; Acetonitrile one water is mobile phase; The detection wavelength is 286nm, and the volume ratio of acetonitrile and water is 70: 30 in the described mobile phase, and regulates pH value to 2.5 with phosphoric acid.
Oil-soluble medicine compositions of the present invention by the compound action of non-polar solven and solubilizing agent, makes the dissolution of oil-soluble composition improve, and bioavailability is good.Used oil-soluble medicine is fenofibrate, probucol, Fluphenazine in the embodiments of the invention.
This oil-soluble medicine compositions that the present invention developed is the oval soft gelatin capsule of salmon pink.The soft capsule material of salmon pink adds appropriate amount of titanium with gelatin, glycerol, water and food coloring is made; Suspension type semi-solid content is to be dispersed in an amount of non-polar solven by after treatment oil-soluble medicine crude drug, adds an amount of solubilizing agent again and is prepared from, and its color depends on the color and luster of raw materials used medicine and non-polar solven.
Description of drawings
The equal number curve contrast of Fig. 1 present embodiment fenofibrate and commercially available fenofibrate dissolution C-T.
The specific embodiment
Below the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein only is used for description and interpretation the present invention, and be not used in qualification the present invention.
Embodiment 1 fenofibrate micropowder, soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois
1-1
Per 1000 compositions meters, take by weighing fenofibrate 20g with pharmacologically active, add medicinal adjuvant isopropyl myristate 18g, all the other are soybean oil and/or Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois 600g, each component is mixed according to the above ratio, under 40-55 ℃ of condition, constantly stir, obtain the fenofibrate oil solution, this fenofibrate oil solution mean cut-off in soft capsule, is made fenofibrate soft gelatin capsule of the present invention.In an embodiment, the fenofibrate micropowder has pharmacologically active, is soluble in non-polar solven, is insoluble in water; Soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois are non-polar solvens, are used to dissolve the fenofibrate micropowder; Isopropyl myristate can be used as solubilizing agent or surfactant, is used for increasing the dissolubility of fenofibrate microgranule at above-mentioned oil solution.
1-2
In per 1000 preparation compositions, described oil-soluble medicine 5g, solubilizing agent isopropyl myristate 10g, ethyl oleate 5g, vegetable oil soybean oil and/or Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois 500g.Method is the same.
1-3
In per 1000 preparation compositions, described oil-soluble medicine 25g, solubilizing agent isopropyl myristate 15, tween 5g, vegetable oil soybean oil and/or Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois 700g.Method is the same.
1-4
In per 1000 preparation compositions, described oil-soluble medicine 50g, solubilizing agent isopropyl myristate 50, polysorbate40 g, PEG400 amount are 60g, vegetable oil soybean oil and/or Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois 900g.Method is the same.
In the various embodiments described above, at least a in soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, the Cortex cocois radicis wet goods vegetable oil, can be used for dissolving the fenofibrate micropowder, isopropyl myristate also can be used for doing the surfactant in the content of the present invention or/and other solubilizing agent can be used as the dissolved solubilizing agent in above-mentioned vegetable oil of fenofibrate micropowder.
Embodiment 2:
The probucol micropowder
Soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois
Isopropyl myristate
2-1
Basic thought of the present invention: per 1000 compositions meters, take by weighing probucol 20g with pharmacologically active, add medicinal adjuvant isopropyl myristate, 18g, all the other are soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois 600g, each component is mixed according to the above ratio, under 40-55 ℃ of condition, constantly stir, obtain the probucol oil solution, this probucol oil solution mean cut-off in soft capsule, is made probucol soft gelatin capsule of the present invention.In an embodiment, the probucol micropowder has pharmacologically active, is soluble in non-polar solven, is insoluble in water; Soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois are non-polar solvens, are used to dissolve the probucol micropowder; Isopropyl myristate, soybean phospholipid can be used as solubilizing agent or surfactant, are used for increasing the dissolubility of probucol microgranule at above-mentioned oil solution.
In the various embodiments described above, at least a in soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, the Cortex cocois radicis wet goods vegetable oil, can be used for dissolving the probucol micropowder, isopropyl myristate can be used as the dissolved solubilizing agent in above-mentioned vegetable oil of probucol micropowder, also can be used for doing the surfactant in the content of the present invention.
2-2
In per 1000 preparation compositions, described oil-soluble medicine 50g, solubilizing agent isopropyl myristate 50, ethyl oleate 20g, Macrogol 600 amount are 80g, vegetable oil soybean oil and/or Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois 900g.Method is the same.
Embodiment 3:
The Fluphenazine micropowder
Soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois
Isopropyl myristate
Basic thought of the present invention: per 1000 compositions meters, take by weighing Fluphenazine 20g with pharmacologically active, add medicinal adjuvant isopropyl myristate 18g, all the other are soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois 600g, each component is mixed according to the above ratio, under 40-55 ℃ of condition, constantly stir, obtain the Fluphenazine oil solution, this Fluphenazine oil solution mean cut-off in soft capsule, is made Fluphenazine soft gelatin capsule of the present invention.In an embodiment, the Fluphenazine micropowder has pharmacologically active, is soluble in non-polar solven, is insoluble in water; Soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois are non-polar solvens, are used to dissolve the Fluphenazine micropowder; Isopropyl myristate can be used as solubilizing agent or surfactant, is used for increasing the dissolubility of Fluphenazine microgranule at above-mentioned oil solution.
In the various embodiments described above, at least a in soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, the Cortex cocois radicis wet goods vegetable oil, can be used for dissolving the Fluphenazine micropowder, isopropyl myristate can be used as the dissolved solubilizing agent in above-mentioned vegetable oil of Fluphenazine micropowder, also can be used for doing the surfactant in the content of the present invention.
Embodiment 4:
The hydroxyprogesterone caproate micropowder
Soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois
Isopropyl myristate
Basic thought of the present invention: per 1000 compositions meters, take by weighing hydroxyprogesterone caproate 20g with pharmacologically active, add medicinal adjuvant isopropyl myristate 18g, all the other are soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois 600g, each component is mixed according to the above ratio, under 40-55 ℃ of condition, constantly stir, obtain the hydroxyprogesterone caproate oil solution, this hydroxyprogesterone caproate oil solution mean cut-off in soft capsule, is made hydroxyprogesterone caproate soft gelatin capsule of the present invention.In an embodiment, the hydroxyprogesterone caproate micropowder has pharmacologically active, is soluble in non-polar solven, is insoluble in water; Soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois are non-polar solvens, are used to dissolve the hydroxyprogesterone caproate micropowder; Isopropyl myristate can be used as solubilizing agent or surfactant, is used for increasing the dissolubility of hydroxyprogesterone caproate microgranule at above-mentioned oil solution.
In the various embodiments described above, at least a in soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, the Cortex cocois radicis wet goods vegetable oil, can be used for dissolving the hydroxyprogesterone caproate micropowder, isopropyl myristate can be used as the dissolved solubilizing agent in above-mentioned vegetable oil of hydroxyprogesterone caproate micropowder, also can be used for doing the surfactant in the content of the present invention.
It should be noted that at last: the above only is the preferred embodiments of the present invention, be not limited to the present invention, although the present invention is had been described in detail with reference to previous embodiment, for a person skilled in the art, it still can be made amendment to the technical scheme that aforementioned each embodiment put down in writing, and perhaps part technical characterictic wherein is equal to replacement.Within the spirit and principles in the present invention all, any modification of being done, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Following experimental example is an example with the fenofibrate soft gelatin capsule, but is not limited thereto.
The standard of embodiment
The present invention made the discriminating of fenofibrate soft gelatin capsule:
(1) get this product content an amount of (being equivalent to fenofibrate 0.1g approximately), put in the separatory funnel, add acetonitrile 20ml, powerful jolting makes the fenofibrate dissolving, discards evaporate to dryness behind the oil phase.Getting solids and carry out organic destruction according to oxygen flask combustion (two appendix VII of Chinese Pharmacopoeia version in 2010 C), is absorption liquid with 0.4% sodium hydroxide solution, adds the dilute sulfuric acid acidify behind all burnt of waiting, and puts coldly, drips the silver nitrate test solution, generates white curdy precipitate; Separate, precipitation adds that ammonia solution is instant to be separated, add rare nitric acid acidify again after, the precipitation repetitive generation.
(2) it is an amount of to get under the assay item need testing solution, adds ethanol dilution and makes the solution that contains 10ug among every 1ml approximately, measures according to spectrophotography (two appendix IVA of Chinese Pharmacopoeia version in 2010), at the wavelength place of 286nm absorption maximum is arranged.
(3) in the chromatogram that writes down under the assay item, the retention time of main peak should be consistent with the retention time at reference substance peak in the need testing solution.
The present invention made the inspection of fenofibrate soft gelatin capsule:
(1) content uniformity is checked item method test down according to soft gelatin capsule content uniformity under two appendix I of Chinese Pharmacopoeia version in 2010 E capsule item, and inner quality standard must not mistake ± 6.5%.
(2) disintegration according in Chinese Pharmacopoeia 2010 editions two appendix XA inspection techniques disintegration to method test under the soft capsule inspection technique disintegration item, be in 1 hour disintegration in simulated gastric fluid.
(3) microbial limit is according to prescriptive procedure inspection in two appendix XI of Chinese Pharmacopoeia version in 2010 J microbial limit test, and by it to microbial limit prescribed limits in the soft capsule promptly: bacterial population must not be crossed 1000 of every 1g; Mycete, yeast count must not be crossed 100 of every 1g; Must not detect among the every 1g of escherichia coli and Pseudomonas aeruginosa.
(4) it is an amount of that destructive testing and related substance ownership precision takes by weighing the fenofibrate reference substance, add acetonitrile dissolving and dilution and make the solution that every 1ml contains 1mg approximately, measure 10ul and inject chromatograph of liquid, the record chromatogram is as checking collection of illustrative plates without destroying the sample related substance; Other gets 3 parts of fenofibrate reference substances, and every part of about 50mg places three 50ml measuring bottles respectively, respectively add the about 45ml of acetonitrile and make dissolving, in the 1st duplicate samples bottle, drip concentrated hydrochloric acid 0.45ml, jolting, add dilution in acetonitrile to scale, shake up, heating in water bath boils 1h, be cooled to room temperature, add dilution in acetonitrile to scale, shake up, measure 10ul and inject chromatograph of liquid, the record chromatogram is checked collection of illustrative plates as destroying the sample related substance through acid; In the 2nd duplicate samples bottle, drip saturated sodium hydroxide solution 3ml, jolting, add dilution in acetonitrile to scale, shake up, heating in water bath boils 1h, be cooled to room temperature, add dilution in acetonitrile to scale, shake up, measure 10ul and inject chromatograph of liquid, the record chromatogram is checked collection of illustrative plates as the related substance that destroys sample through alkali; In the 3rd duplicate samples bottle, add dilution in acetonitrile to scale, shake up, heated and boiled 1h is cooled to room temperature, adds dilution in acetonitrile to scale, shakes up, and measures 10ul and injects chromatograph of liquid, and the record chromatogram is as checking collection of illustrative plates through heat damage sample related substance; To put in the constant temperature lamp box behind (5 ℃, illumination 4500LX) illumination 24h without destroying sample, and take out, and put to room temperature, and add dilution in acetonitrile to scale, and shake up, and measure 10ul and inject chromatograph of liquid, the record chromatogram is checked collection of illustrative plates as photo damage sample related substance.
For confirm that further what material the impurity that fenofibrate produces is after destroying, carried out following test then.
Precision takes by weighing fenofibrate acid about 50mg, the about 50mg of fenofibrate phenol, the about 50mg of fenofibrate reference substance, puts respectively in 3 50ml measuring bottles, adds the acetonitrile dissolving and is diluted to scale, shakes up.Each precision is measured impurity solution 5ml, puts respectively in 2 100ml measuring bottles, adds dilution in acetonitrile to scale, shakes up.Measure each 10ul successively, inject chromatograph of liquid respectively, the record chromatogram.
Experimental result shows that this product is more stable under illumination, heating and acid condition, easily degraded under alkali condition, and catabolite is mainly fenofibrate acid.Existing related substance inspection technique can effectively detect catabolite, and separating degree is good.
(5) related substance this product content, precision takes by weighing in right amount (being equivalent to fenofibrate 40mg approximately), put in the tool plug centrifuge tube, extract 4 times (the 1-3 time each 15ml, the 4th 10ml) with the acetonitrile jolting, each jolting is after 10 minutes centrifugal 15 minutes (4500rad/min), and with dropper with in the acetonitrile liquid dislocation 100ml volumetric flask, merge extractive liquid, adds dilution in acetonitrile to scale, shake up, as need testing solution (0.4mg/ml); Precision is measured 1ml, puts in the 100ml volumetric flask, adds dilution in acetonitrile to scale, shakes up, in contrast solution (4ug/ml); Other gets fenofibrate acid, and fenofibrate phenol reference substance is an amount of, and precision claims fixed, adds the also quantitative dilution of acetonitrile dissolving and makes the solution that contains 1mg among every 1ml, product solution in contrast.According to the chromatographic condition under the assay item, measure 10 μ l contrast solutions and inject chromatograph of liquid, regulate detection sensitivity, the peak height that makes the main constituent chromatographic peak is the 10%-20% of full scale.Precision is measured each 10 μ l of need testing solution, contrast solution and reference substance solution again, inject chromatograph of liquid respectively, the record chromatogram is to 2 times of the main constituent retention time, in the need testing solution if any with reference substance solution in the corresponding chromatographic peak of two main peaks, its peak area must not distinguish greater than 0.1% of the peak area of respective peaks in the reference substance solution; Other each impurity peak area and, must not be greater than contrast solution main peak area 0.5%.
Assay
Measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2010).
The mobile phase screening is selected the mobile phase of good separating effect in order to separate, analyze related substance in this product better, and following condition is screened.
Wherein, water-acetonitrile (30: 70) pH2.5 separating effect best (separating degree of main peak and main impurity peaks is more than 3); Main peak appearance time moderate (11～14 minutes); Main peak peak shape symmetry (tailing factor T=1.01).So selecting water-acetonitrile (30: 70), regulating pH to 2.5 with phosphoric acid is mobile phase.
It is an amount of that the fenofibrate reference substance is got in the selection of detection wavelength, add acetonitrile dissolving and dilution and make the solution that contains 12ug among every 1ml approximately, measure according to spectrophotography (two appendix IV of Chinese Pharmacopoeia version in 2000 A), ultraviolet absorption curve in scanning wavelength 200nm to the 400nm scope, maximum absorption wavelength are 285nm～287nm.So selecting to detect wavelength is 286nm.
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; Acetonitrile one water (regulating pH value to 2.5 with phosphoric acid) (70: 30) is mobile phase; The detection wavelength is 286nm.Number of theoretical plate calculates by the fenofibrate peak should be not less than 2000.
Algoscopy is got content under the content uniformity item, mix homogeneously, and precision takes by weighing in right amount (being equivalent to fenofibrate 10mg approximately), put in the tool plug centrifuge tube, with acetonitrile supersound extraction 4 times (the 1-3 time each 15ml, the 4th 10ml), each after ultrasonic 10 minutes centrifugal 15 minutes (4500rad/min), and with dropper with in the acetonitrile liquid dislocation 100ml volumetric flask, merge extractive liquid, adds dilution in acetonitrile to scale, shake up, molten as test sample, the accurate 10ul of absorption of liquid injects chromatograph of liquid, the record chromatogram; It is an amount of that other gets reference substance, and accurate title is fixed, adds acetonitrile dissolving and dilution and make the solution that contains 0.1mg among every 1ml approximately, measures with method, presses external standard method with calculated by peak area, promptly.
(1) it is an amount of that the blank sample content is got in the interference of solvent and blank content, 120mg decided in accurate title, put in the tool plug centrifuge tube, with 4 (the 1-3 time each 15ml of acetonitrile supersound extraction, the 4th 10ml), each after ultrasonic 10 minutes centrifugal 15 minutes (4500rad/min), and with dropper with in the acetonitrile liquid dislocation 100ml volumetric flask, merge extractive liquid, adds dilution in acetonitrile to scale, shake up, draw 10ul and inject chromatograph of liquid, record chromatograph to 30 minute had between 3 minutes the tiny adjuvant and solvent peak, do not have other chromatographic peaks, show that solvent and blank content (adjuvant) are noiseless to measuring.
(2) linear relationship test precision takes by weighing the about 50mg of fenofibrate reference substance and puts in the 100ml measuring bottle, add the acetonitrile dissolving and be diluted to scale, shake up, No. 1 is blank (10ml acetonitrile), and precision measures 1.0,3.0,5.0,7.0,9.0,10.0ml, places 6 10ml measuring bottles respectively 2-7 number, except that No. 7 measuring bottles just to scale, all the other 5 measuring bottles all add dilution in acetonitrile to scale, shake up, as need testing solution.Each precision is measured 10ul and is injected chromatograph of liquid successively, the record chromatographic peak area, and the parallel sample introduction of every duplicate samples 2 times calculates the chromatographic peak area meansigma methods.With the chromatographic peak area meansigma methods is abscissa (X), is ordinate (Y) with sample size (ug), calculates linear equation, linearly dependent coefficient and square value.
(3) precision test precision takes by weighing the about 20mg of fenofibrate soft gelatin capsule content, put in the tool plug centrifuge tube, with acetonitrile supersound extraction 4 times (the 1-3 time each 15ml, the 4th 10ml), each after ultrasonic 10 minutes centrifugal 15 minutes (4500rad/min), and with dropper with in the acetonitrile liquid dislocation 100ml volumetric flask, merge extractive liquid, adds dilution in acetonitrile to scale, shake up, measure 10ul and inject chromatograph of liquid, record chromatogram, continuous sample introduction 6 times.
(3) liquid stability test precision to be measured takes by weighing fenofibrate soft gelatin capsule content 20mg, put in the tool plug centrifuge tube, with acetonitrile supersound extraction 4 times (the 1-3 time each 15ml, the 4th 10ml), each after ultrasonic 10 minutes centrifugal 15 minutes (4500rad/min), and with dropper with in the acetonitrile liquid dislocation 100ml volumetric flask, merge extractive liquid, adds dilution in acetonitrile to scale, shake up, measure 10ul and inject chromatograph of liquid, the record chromatogram, sample introduction 1 time was repeated at every interval in 2 hours.
(4) the recovery test precision takes by weighing 9 parts of the blank soft gelatin capsule contents made in prescription ratio and existing preparation technology, every part is about 30mg, place 9 tool plug centrifuge tubes respectively 1-9 number, precision takes by weighing 9 parts of fenofibrate reference substances (sample weighting amount is 20mg ± 20%), place above-mentioned 9 tool plug centrifuge tubes respectively, with glass rod it is stirred evenly earlier, with acetonitrile supersound extraction 4 times (the 1-3 time each 15ml, the 4th 10ml), each after ultrasonic 10 minutes centrifugal 15 minutes (4500rad/min), and with dropper with in the acetonitrile liquid dislocation 100ml volumetric flask, merge extractive liquid, adds dilution in acetonitrile to scale, shakes up, measure 10ul and inject chromatograph of liquid successively, the record chromatographic peak area; Other gets the about 10mg of fenofibrate reference substance, puts in the 100ml measuring bottle, adds the acetonitrile dissolving and is diluted to scale, shakes up, and tests with method, presses external standard method with the calculated by peak area response rate.
(5) the precision test in the different time, uses different instruments that the fenofibrate soft gelatin capsule is carried out assay for investigating the influence of random fluctuation factor to precision in the middle of.
Dissolution
Simulated gastric fluid: get dilute hydrochloric acid 16.4ml, add about 800ml of water and pepsin 10g, after shaking up, thin up becomes 1000ml, promptly.
The principal agent fenofibrate is insoluble in water in selection this product of dissolution medium, does not all meet sink conditions in water, simulated gastric fluid, simulated intestinal fluid, 20% alcoholic solution, 5% sodium dodecyl sulfate solution.In order to seek the solvent that meets sink conditions, again following solvent is tested.
Condition 1 contains 5% dodecyl sodium sulfate, 20% alcoholic acid solution;
Condition 2 contains 5% dodecyl sodium sulfate, 25% alcoholic acid solution;
Condition 3 contains the solution of 5% dodecyl sodium sulfate, 20% acetonitrile;
Condition 4 polyoxyethylene sorbitan monoleates-water 40: 60
Condition 6 polyoxyethylene sorbitan monoleates-water 30: 70
Condition 7 polyoxyethylene sorbitan monoleates-water-ethanol 30: 60: 10
40: 60 (containing 1% pepsin) of condition 8 polyoxyethylene sorbitan monoleates-water
And 10 editions officinal leaching conditions are 1.0% sodium dodecyl sulfate solution 1000ml, 120rad/min, 60min.
Final optimization test condition is: adopt 2010 editions two transfer basket methods of Chinese Pharmacopoeia to carry out external dissolution test, selecting the stripping mediator is concentration 5% sodium dodecyl sulfate solution, 37 ° of temperature, rotating speed 50r/min, detect 5min, 10min, 20min, 30min, 40min, 60min respectively, the release conditions that 120min is ordered.
The result shows: release reaches 85%, meets the pharmacopeia requirement.
Slaking test:
Enteric coated preparation to the soft capsule among the present invention or hard capsule or liquid capsule outsourcing casing carries out slaking test by among 2010 editions pharmacopeia appendix XA enteric coated capsule being carried out the inspection technique of disintegration.With preferred embodiment fenofibrate enteric soft gelatin capsule, probucol enteric soft gelatin capsule is an example
Experimental result sees Table 7
| Situation 2h in the hydrochloric acid solution | Situation in the simulated intestinal fluid | |
| Fenofibrate enteric soft gelatin capsule (25mg) | Free from flaw, softening, foaming phenomenon | 13min promptly breaks, and 21min dissolves fully |
| Fenofibrate enteric soft gelatin capsule (50mg) | Free from flaw, softening, foaming phenomenon | 15min promptly breaks, and 22min dissolves fully |
| Probucol enteric soft gelatin capsule (50mg) | Free from flaw, softening, foaming phenomenon | 10min promptly breaks, and 18min dissolves fully |
Stability test
It is 3500LX that the soft gelatin capsule that makes respectively in the above embodiment of the present invention is exposed to illumination, and temperature is respectively room temperature, 40 ℃ and 25 ℃, and humidity was respectively under the condition of RH92.5% and RH75% each 10 days.Soft gelatin capsule of the present invention with the sealing preservation compares from aspects such as character, content color and luster, cracked property, disintegration, assay and chromatograph inspection degradation products respectively again, comparing result shows, descends exposed each character of soft gelatin capsule of the present invention basicly stable through illumination and different temperatures, damp condition.
In addition, soft gelatin capsule of the present invention is packed, and is that 40 ℃, humidity are to quicken transhipment six months under the condition of RH75% in temperature, stores at ambient temperature 24 months simultaneously, and regularly sample is observed mensuration according to the accurate index of investigating of default matter temperature scale, find that each character of sample is basicly stable.
The bioequivalence experiment
(1), the relative bioavailability experimentation of preferred embodiment fenofibrate soft gelatin capsule among the present invention:
This research is subjects with 8 of beasle dogs, adopt the dual crossing test method, difference single dose intersection is oral administration 1 (containing fenofibrate 50mg) of fenofibrate soft gelatin capsule or 1 of commercially available fenofibrate soft gelatin capsule (containing fenofibrate 200mg) on an empty stomach, adopt the drug level in the high effective liquid chromatography for measuring different time blood plasma, ask data according to blood drug level-time, tried to achieve main pharmacokinetic parameter.
Result of calculation shows:
Among the present invention in the preferred embodiment fenofibrate soft gelatin capsule Tmax of fenofibrate be 4.688 ± 3.779 (h), cmax is 21.027 ± 16.766 (ug/ml), T1/2 is 7.563 ± 5.093 (h), AUC
0～24Be 115.192 ± 38.192 (ug.h/ml), AUC
0～ ∞Be 137.94 ± 64.645 (ug.h/ml).
The Tmax of the commercially available fenofibrate soft gelatin capsule of reference preparation is 4.036 ± 2.678 (h), and cmax is 17.323 ± 9.006 (ug/ml), T1, and 2 is 9.151 ± 4.853 (h), AUC
0～24Be 112.221 ± 57.222 (ug.h/ml), AUC
0～∞Be 299.153 ± 367.561 (ug.h/ml).
Concrete outcome sees Table 1, table 2, table 3
Table 1 single dose gives the pharmacokinetic parameter behind the preferred embodiment fenofibrate soft gelatin capsule (A) among the present invention
| Pharmacokinetic parameters (A medicine) | ||||||
| Brother examination person numbering | AUCt | ?AUCi | ?AUCt/AUCi(％) | ?Cmax | ?Tmax | ?T1/2 |
| ?1 | ?121.288 | ?133.364 | ?90.945 | ?14.049 | ?9 | ?7.801 |
| ?2 | ?134.186 | ?264.303 | ?50.77 | ?10.384 | ?4.5 | ?19.468 |
| ?3 | ?121.921 | ?122.347 | ?99.652 | ?27.499 | ?3 | ?2.864 |
| ?4 | ?138.831 | ?154.719 | ?89.731 | ?24.194 | ?2 | ?6.49 |
| ?5 | ?55.602 | ?60.93 | ?91.255 | ?8.108 | ?3 | ?7.603 |
| ?6 | ?154.124 | ?156.206 | ?98.667 | ?13.352 | ?12 | ?4.259 |
| ?7 | ?55.743 | ?58.851 | ?94.719 | ?11.656 | ?2.5 | ?5.375 |
| ?8 | ?139.838 | ?152.803 | ?91.515 | ?58.978 | ?1.5 | ?6.643 |
| ?Mean | ?115.192 | ?137.94 | ?88.407 | ?21.027 | ?4.688 | ?7.563 |
| ?SD | ?38.192 | ?64.645 | ?15.648 | ?16.766 | ?3.779 | ?5.093 |
| ?RSD/％ | ?33.2 | ?46.9 | ?17.7 | ?79.7 | ?80.6 | ?67.3 |
Table 2 single dose gives the pharmacokinetic parameter behind the commercially available fenofibrate soft gelatin capsule (R)
| Pharmacokinetic parameters (R medicine) | ||||||
| Experimenter's numbering | AUCt | AUCi | AUCt/AUCi(％) | Cmax | Tmax | T1/2 |
| 1 | 51.526 | 58.105 | 88.677 | 28.254 | 2.5 | 8.572 |
| 2 | 84.376 | 101.196 | 83.379 | 13.706 | 7 | 6.171 |
| 3 | 130.727 | 243.684 | 53.646 | 15.019 | 2.5 | 9.862 |
| 4 | 70.769 | 1178.795 | 6.004 | 12.35 | 2.5 | 1.72 |
| 5 | 145.173 | 151.162 | 96.038 | 16.167 | 2.5 | 7.644 |
| 6 | 44.439 | 100.597 | 44.176 | 6.18 | 1.5 | 18.368 |
| 7 | 182.562 | 210.922 | 86.554 | 33.566 | 5 | 12.602 |
| 8 | 188.197 | 348.76 | 53.962 | 13.345 | 9 | 8.267 |
| Mean | 112.221 | 299.153 | 64.054 | 17.323 | 4.063 | 9.151 |
| SD | 57.222 | 367.561 | 30.435 | 9.006 | 2.678 | 4.853 |
| RSD/％ | 51 | 122.9 | 47.5 | 52 | 65.9 | 53 |
The relative bioavailability of table 3 fenofibrate soft gelatin capsule is calculated
Adopt the DAS statistical analysis software, utilization dual crossing design method of analysis of variance, statistical analysis and evaluation of bioequivalence are carried out to above-mentioned main pharmacokinetic parameter in two-one sided test and (1～2 α) confidence interval, and the result shows: by the average T max of test preparation, and cmax, AUC
0～24All more than or equal to control formulation.Fenofibrate soft gelatin capsule of the present invention is 146.7 ± 109.4% to the average relative bioavailability F of commercially available fenofibrate soft gelatin capsule, and 90% of its bioavailability parameter value crediblely is limited to 58.5%～204.8%.As seen two kinds of preparation bioavailability inequivalences, test preparation 25mg is than reference preparation 200mg bioavailability height, and its Canis familiaris L. bioavailability is more than 4 times of commercially available fenofibrate soft gelatin capsule.See Fig. 1.
(2), the relative bioavailability experimentation of preferred embodiment probucol soft gelatin capsule among the present invention:
This research is subjects with 4 of beasle dogs, adopt the dual crossing test method, difference single dose intersection is oral administration 1 (containing probucol 50mg) of probucol soft gelatin capsule or 4 of commercially available probucol sheets (containing probucol 500mg) on an empty stomach, adopt the drug level in the high effective liquid chromatography for measuring different time blood plasma, according to blood drug level-time data, tried to achieve main pharmacokinetic parameter.
Result of calculation shows:
The Tmax of preferred embodiment probucol soft gelatin capsule (50mg) is 7.5 ± 1 (h) among the present invention, and cmax is 254.182 ± 358.82 (ug/ml), and T1/2 is 1.775 ± 0.899 (h), AUC
0～24Be 613.094 ± 796.315 (ug.h/ml), AUC
0～∞Be 2027.43 ± 3165.858 (ug.h/ml).
The Tmax of the commercially available probucol sheet of reference preparation (500mg) is 6.75 ± 2.5 (h), and cmax is 128.443 ± 73.838 (ug/ml), and T1/2 is 4.685 ± 7.007 (h), AUC
0～24Be 321.23 ± 85.995 (ug.h/ml), AUC
0～∞Be 761.534 ± 876 (ug.h/ml).
Concrete outcome sees Table 4, table 5, table 6
Table 4 single dose gives the pharmacokinetic parameter behind the preferred embodiment probucol soft gelatin capsule (A) among the present invention
| Pharmacokinetic parameters (A medicine) | ||||||
| Experimenter's numbering | AUCt | AUCi | AUCt/AUCi(％) | Cmax | Tmax | T1/2 |
| 1 | 201.757 | 361.801 | 55.765 | 55.561 | 8 | 1.643 |
| 2 | 1807.165 | 6770.148 | 26.693 | 791.382 | 6 | 0.693 |
| 3 | 199.215 | 307.18 | 64.853 | 63.64 | 8 | 1.88 |
| 4 | 244.239 | 670.593 | 36.421 | 106.143 | 8 | 2.883 |
| Mean | 613.094 | 2027.43 | 45.933 | 254.182 | 7.5 | 1.775 |
| SD | 796.315 | 3165.858 | 17.467 | 358.82 | 1 | 0.899 |
| RSD/％ | 129.9 | 156.2 | 38 | 141.2 | 13.3 | 50.7 |
Table 5 single dose gives the pharmacokinetic parameter behind the commercially available probucol sheet 4*125mg (R)
| Pharmacokinetic parameters (R medicine) | ||||||
| Experimenter's numbering | AUCt | AUCi | AUCt/AUCi(％) | Cmax | Tmax | T1/2 |
| 1 | 426.755 | 457.193 | 93.342 | 231.834 | 8 | 1.989 |
| 2 | 340.249 | 2068.596 | 16.448 | 79.598 | 8 | 15.162 |
| 3 | 220.666 | 222.36 | 99.239 | 71.229 | 3 | 0.848 |
| 4 | 297.252 | 297.987 | 99.753 | 131.11 | 8 | 0.742 |
| Mean | 321.23 | 761.534 | 77.196 | 128.443 | 6.75 | 4.685 |
| SD | 85.995 | 876.854 | 40.603 | 73.838 | 2.5 | 7.007 |
| RSD/％ | 26.8 | 115.1 | 52.6 | 57.5 | 37 | 149.6 |
The relative bioavailability of table 6 probucol soft gelatin capsule is calculated
Adopt the DAS statistical analysis software, utilization dual crossing design method of analysis of variance, statistical analysis and evaluation of bioequivalence are carried out to above-mentioned main pharmacokinetic parameter in two-one sided test and (1～2 α) confidence interval, and the result shows: by the average T max of test preparation, and Cmax, AUC
0～24All be far longer than control formulation.Probucol soft gelatin capsule of the present invention is 187.7.7 ± 229.7% to the average relative bioavailability F of commercially available probucol sheet, and 90% of its bioavailability parameter value crediblely is limited to 30.1%～452.9%.As seen two kinds of preparation bioavailability inequivalences, test preparation 50mg is than reference preparation 500mg bioavailability height, and its Canis familiaris L. bioavailability is more than 10 times of commercially available probucol sheet.
Claims (14)
1. the oil-soluble medicine compositions comprises content and outer covering material, the oil solution of described content for being made by oil-soluble medicine and adjuvant; Described adjuvant is non-polar solven and solubilizing agent, and described non-polar solven is vegetable oil, animal oil or polyoxyl 40 hydrogenated castor oil; Described solubilizing agent is isopropyl myristate and/or ethyl oleate, tween, PEG400, Macrogol 600.
2. oil-soluble medicine compositions according to claim 1, described vegetable oil is one or more in Oleum Arachidis hypogaeae semen, soybean oil, Oleum Brassicae campestris, Semen Maydis oil, olive oil, Oleum Helianthi, Oleum sesami, Semen Lini oil, Oleum Gossypii semen, Testa oryzae oil, Oleum Cocois, camellia seed oil, low erucic acid rapeseed oil, Fructus Zanthoxyli oil, the chilli oil, and described animal oil is one or more in Adeps Sus domestica, Adeps Bovis seu Bubali, Adeps Caprae seu ovis, chicken oil, the duck oil.
3. oil-soluble medicine compositions according to claim 1, described solubilizing agent are isopropyl myristate and/or ethyl oleate, tween, PEG400, Macrogol 600.
4. oil-soluble medicine compositions according to claim 1 in per 1000 preparation compositions, contains oil-soluble medicine 2-70g, solubilizing agent 1-210g, vegetable oil 400～1000g.
5. oil-soluble medicine compositions according to claim 1, described oil-soluble medicine are fenofibrate, probucol, undecylenic acid, testosterone undecanoate, diethylstilbestrol, hydroxyprogesterone caproate, Testosterone Propionate, methyltestosterone, nandrolone phenylpropionate, estradiol benzoate, Fluphenazine or vitamin D3.
6. oil-soluble medicine compositions according to claim 5, in per 1000 preparation compositions, described oil-soluble medicine 5g, solubilizing agent is one or more 15g in isopropyl myristate, ethyl oleate, tween, PEG400, the Macrogol 600, vegetable oil 500-900g.
7. oil-soluble medicine compositions according to claim 5, in per 1000 preparation compositions, described oil-soluble medicine 25g, solubilizing agent is one or more 20g in isopropyl myristate, ethyl oleate, tween, PEG400, the Macrogol 600, vegetable oil 500-900g.
8. oil-soluble medicine compositions according to claim 5, in per 1000 preparation compositions, described oil-soluble medicine 50g, solubilizing agent is one or more 150g in isopropyl myristate, ethyl oleate, tween, PEG400, the Macrogol 600, vegetable oil 500-900g.
9. oil-soluble medicine compositions according to claim 1, its preparation formulation are soft capsule, liquid capsule, hard capsule or drop pill.
10. oil-soluble medicine compositions according to claim 9, described outer covering material contains gelatin, or gelatin and propylene glycol or gelatin and glycerol.
11. being capsule, oil-soluble medicine compositions according to claim 1, its preparation formulation wrap enteric coating outward again.
12. the described oil-soluble medicine preparation of compositions of claim 11 method, comprise: take by weighing each component of content in proportion, its mixing is stirred evenly, obtain oil solution, oil solution is got the filling of an amount of usefulness revolving die formula soft gelatin capsule maker in capsule, with enteric coating in soft capsule or liquid capsule or hard capsule or the drop pill outsourcing.
13. preparation method according to claim 12, described mixing stir evenly under temperature 10-65 ℃ condition and stir, and adopt ultrasonic assist in dissolving when described mixing stirs evenly.
14. the content assaying method of oil-soluble medicine compositions, described medicine is a fenofibrate, it is characterized in that: with octadecylsilane chemically bonded silica is filler; Acetonitrile one water is mobile phase; The detection wavelength is 286nm, and the volume ratio of acetonitrile and water is 70: 30 in the described mobile phase, and regulates pH value to 2.5 with phosphoric acid.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101577525A CN102247598A (en) | 2011-06-13 | 2011-06-13 | Oil-soluble drug composition |
| PCT/CN2012/072013 WO2012171364A1 (en) | 2011-06-13 | 2012-03-07 | Oil-soluble pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101577525A CN102247598A (en) | 2011-06-13 | 2011-06-13 | Oil-soluble drug composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102247598A true CN102247598A (en) | 2011-11-23 |
Family
ID=44975400
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011101577525A Pending CN102247598A (en) | 2011-06-13 | 2011-06-13 | Oil-soluble drug composition |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN102247598A (en) |
| WO (1) | WO2012171364A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103257192A (en) * | 2013-05-08 | 2013-08-21 | 北京满格医药科技有限公司 | Dissolution rate determination method of soft capsules |
| CN105362278A (en) * | 2014-09-01 | 2016-03-02 | 苏州系统医学研究所 | Preparation containing 25-hydroxycholesterol and preparation method thereof and anti-virus application |
| CN107782810A (en) * | 2016-08-26 | 2018-03-09 | 人福普克药业（武汉）有限公司 | The method for detecting calcitriol content in calcitriol soft capsule |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107603729A (en) * | 2017-09-30 | 2018-01-19 | 三江县善茶轩工艺品有限公司 | The preparation method of camellia seed oil |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101484138A (en) * | 2006-03-07 | 2009-07-15 | 诺瓦瓦克斯有限公司 | Nanoemulsions of poorly soluble pharmaceutical active ingredients and methods of making the same |
| CN101711738A (en) * | 2008-10-08 | 2010-05-26 | 中国人民解放军军事医学科学院毒物药物研究所 | Oral pharmaceutical composition of Fenofibrate |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1165141A2 (en) * | 1999-03-31 | 2002-01-02 | Abbott Laboratories | Novel formulations comprising lipid-regulating agents |
| CN1261097C (en) * | 2002-02-09 | 2006-06-28 | 浙江万联药业有限公司 | Nisoldipine capsule composition |
| CN101181282B (en) * | 2007-07-25 | 2010-05-19 | 中国药科大学 | Hydroxyl radical carthamin yellow carthamus A soft capsule with high bioavailability and preparation method thereof |
| JP2011526621A (en) * | 2008-07-03 | 2011-10-13 | パナセア バイオテック リミテッド | Fenofibrate formulation with increased oral bioavailability |
| CN101416954A (en) * | 2008-12-08 | 2009-04-29 | 贾祥波 | Nitrendipine self-emulsification soft capsules and preparation method thereof |
-
2011
- 2011-06-13 CN CN2011101577525A patent/CN102247598A/en active Pending
-
2012
- 2012-03-07 WO PCT/CN2012/072013 patent/WO2012171364A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101484138A (en) * | 2006-03-07 | 2009-07-15 | 诺瓦瓦克斯有限公司 | Nanoemulsions of poorly soluble pharmaceutical active ingredients and methods of making the same |
| CN101711738A (en) * | 2008-10-08 | 2010-05-26 | 中国人民解放军军事医学科学院毒物药物研究所 | Oral pharmaceutical composition of Fenofibrate |
Non-Patent Citations (1)
| Title |
|---|
| 何勇等: "HPLC法测定非诺贝特胶囊的含量", 《安徽医药》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103257192A (en) * | 2013-05-08 | 2013-08-21 | 北京满格医药科技有限公司 | Dissolution rate determination method of soft capsules |
| CN105362278A (en) * | 2014-09-01 | 2016-03-02 | 苏州系统医学研究所 | Preparation containing 25-hydroxycholesterol and preparation method thereof and anti-virus application |
| CN107782810A (en) * | 2016-08-26 | 2018-03-09 | 人福普克药业（武汉）有限公司 | The method for detecting calcitriol content in calcitriol soft capsule |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012171364A1 (en) | 2012-12-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Kazi et al. | Enhancing oral bioavailability of apigenin using a bioactive self-nanoemulsifying drug delivery system (Bio-SNEDDS): In vitro, in vivo and stability evaluations | |
| CN102470103B (en) | Pharmaceutical composition as hcv protease inhibitors | |
| Abrahamsson et al. | Food effects on tablet disintegration | |
| Woo et al. | Reduced food-effect and enhanced bioavailability of a self-microemulsifying formulation of itraconazole in healthy volunteers | |
| Basavaraj et al. | Improved oral delivery of resveratrol using proliposomal formulation: investigation of various factors contributing to prolonged absorption of unmetabolized resveratrol | |
| CN101019833A (en) | Oil-in-oil nonaqueous microemulsion used as medicine carrier and its medicine prepn | |
| CN102247598A (en) | Oil-soluble drug composition | |
| Chudasama et al. | Role of lipid-based excipients and their composition on the bioavailability of antiretroviral self-emulsifying formulations | |
| Parakh et al. | Development of self-microemulsifying drug delivery system of mebendazole by spray drying technology: characterization, in vitro and in vivo evaluation | |
| Agarwal et al. | Powdered self-emulsified lipid formulations of meloxicam as solid dosage forms for oral administration | |
| CN104224787A (en) | Compound antimalarial composition | |
| CN102046202A (en) | Stabilizing lipid compositions for oral pharmaceutical agents | |
| Lee et al. | Formulation and in vivo evaluation of a solid self-emulsifying drug delivery system using oily liquid tocotrienols as model active substance | |
| CN106361719A (en) | Eltrombopag liquid capsule and preparation method thereof | |
| Brun et al. | Beyond-use dates assignment for pharmaceutical preparations: example of low-dose amiodarone capsules | |
| CN110478347B (en) | HC-1119 preparation, preparation method and application thereof | |
| Biswal et al. | Effects of carbohydrate polymers in self-microemulsified tablets on the bioavailability of atorvastatin: In vitro–in vivo study | |
| CN112741819B (en) | Fluoxetine hydrochloride capsule and preparation method thereof | |
| Taha et al. | Preparation, in vitro and in vivo evaluation of solid-state self-nanoemulsifying drug delivery system (SNEDDS) of vitamin A acetate | |
| Bhusari et al. | Development of Darunavir proliposome powder for oral delivery by using Box–Bhenken design | |
| Gohel et al. | Resolving issues of content uniformity and low permeability using eutectic blend of camphor and menthol | |
| Rao et al. | Formulation and evaluation of a novel capsule-in-a-capsule technology for biphasic delivery of lornoxicam in the treatment of migraine | |
| Stegemann et al. | Hard capsules in modern drug delivery | |
| CN102406600A (en) | Decoquinate solution and preparation method thereof | |
| CN113786385B (en) | Artemisinin self-emulsifying drug release system and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20111123 |