CN105534987A - Aprepitant oral pharmaceutical preparation - Google Patents
Aprepitant oral pharmaceutical preparation Download PDFInfo
- Publication number
- CN105534987A CN105534987A CN201610111912.5A CN201610111912A CN105534987A CN 105534987 A CN105534987 A CN 105534987A CN 201610111912 A CN201610111912 A CN 201610111912A CN 105534987 A CN105534987 A CN 105534987A
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- component
- aprepitant
- oral drug
- cellulose
- drug preparation
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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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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)
- Medicinal Preparation (AREA)
Abstract
The invention discloses an aprepitant oral pharmaceutical preparation. The aprepitant oral pharmaceutical preparation comprises 15wt%-25wt% of aprepitant, 45wt%-75wt% of hydroxypropyl methylcellulose phthalate/hydroxypropyl methylcellulose acetate succinate, 10wt%-25wt% of microcrystalline cellulose, lactose or mannitol, 2wt%-8wt% of low-substituted hydroxypropyl cellulose as well as croscarmellose sodium and/or crospovidone, 0-2wt% of silicon dioxide and/or talc and 0-2wt% of magnesium stearate. The pharmaceutical preparation can be prepared in a form of tablets or capsules andhas high stability and good bioavailability.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, particularly relate to a kind of aprepitant oral drug preparation.
Background technology
Aprepitant, full 5-[2 (R)-[1 (R)-[3,5-bis-(trifluoromethyl) phenyl] ethyoxyl]-3 (S)-(4-fluorophenyl) morpholine-4-ylmethyl]-3, the 4-dihydro-2H-1 by name of chemistry, 2,4-triazole-3-ketone; Aprepitant; 5-(2 (R)-(1 (R)-(3,5-bis-(trifluoromethyl) phenyl) ethyoxyl)-3 (S)-(4-fluorophenyl) morpholine-4-ylmethyl)-3,4-dihydro-2H-1,2,4-triazole-3-ketone, a kind of selectivity high-affinity Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2/neurokinine-1 (NK1) acceptor inhibitor, very low to the affinity of 5-hydroxy tryptamine (5HT3), dopamine and cortical hormone receptor.This medicine is by blood brain barrier, with NK1 receptors bind in brain, use as Bendectin and emetic clinically, cause the acute and Delayed onset Nausea and vomiting caused by telling property anticancer chemotherapeutic agent (comprising High-dose Cisplatin Chemotherapy therapeutic scheme) in particular for height.The molecular formula of aprepitant: C23H21F7N4O3, molecular weight: 534.4267, structural formula is:
After oral aprepitant, peak time (Tmax) is 4 hours, and the pharmacokinetic properties of this medicine is non-linear, and plasma protein binding rate is greater than 95%.This medicine distribution volume is large, and remove mainly through drug metabolism, metabolic pathway comprises CYP3A4 (main path), CYP1A2 and CYP2C19 (minor path).Aprepitant is water-soluble hardly, therefore existing aprepitant tablet commercially adopts grinding technique that aprepitant raw material particle size is reduced to Nano grade, be prepared into nano suspension, improve the oral absorption of aprepitant, but the cost of this technology is very high, and have the debris contamination of grinder, limit promoting the use of of aprepitant.Therefore it is very urgent for studying novel aprepitant oral drug preparation.
Summary of the invention
Goal of the invention of the present invention is the shortcoming in order to overcome above-mentioned background technology, a kind of aprepitant (apprepitant) oral drug preparation is provided, it can increase the dissolubility of aprepitant in Physiological Medium and dissolution rate significantly, and then improves its bioavailability.
A kind of aprepitant oral drug preparation, comprises following component:
Component A: aprepitant 15-25wt%
Component B: Hydroxypropyl methyl cellulose phtalate and/or Hydroxypropyl Methyl Cellulose Phthalate 45-75wt%
Component C: microcrystalline Cellulose, lactose and/or mannitol 10-25wt%
Component D: low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose and/or crospovidone 2-8wt%
Component E: silicon dioxide and/or Talcum 0-2wt%
Component F: magnesium stearate 0-2wt%.
Further, said preparation comprises following component:
Component A: aprepitant 18-23wt%
Component B: Hydroxypropyl methyl cellulose phtalate and/or Hydroxypropyl Methyl Cellulose Phthalate 60-70wt%
Component C: microcrystalline Cellulose, lactose and/or mannitol 11-20wt%
Component D: low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose and/or crospovidone 3-6wt%
Component E: silicon dioxide and/or Talcum 0.5-2wt%
Component F: magnesium stearate 1-2wt%.
Further, the weight ratio of component A: component C: component F is 1:(1-1.1): (0.025-0.055).
Further, described preparation is capsule or tablet.
Further, in described preparation, per unit dosage contains the aprepitant of 80-85mg.
Further, the capsule shells that uses of the described preparation capsule shells that is gelatin and/or hydroxypropyl emthylcellulose.
Present invention also offers the preparation method of above-mentioned aprepitant oral drug preparation, comprise the steps:
(1) component A and component B is dissolved in dehydrated alcohol, drying under reduced pressure, dry thing is crossed 150 mesh sieves and obtains solid dispersion, for subsequent use;
(2) component C is crossed 150 mesh sieves to component F, for subsequent use;
(3) take the solid dispersion after sieving, add component C successively wherein to component F, mix homogeneously, tabletting or encapsulation capsule.
The aprepitant oral drug preparation that the present invention adopts special formulation to prepare effectively can improve the dissolution rate of aprepitant, has the stability of height, the bioavailability that can increase activated feedstock medicine aprepitant and the transmutability reduced in absorption process.These oral drugs can be prepared into tablet or capsule, reduce production cost, have filled up the market vacancy.
Accompanying drawing explanation
Fig. 1 is the stripping concentration schematic diagram of aprepitant in biorelevant media in embodiment 1-3.
Fig. 2 is the concentration schematic diagram in embodiment 1-3 in the Dog Plasma of aprepitant under empty stomach condition.
Detailed description of the invention
Only the present invention is described in further detail for embodiment below, but should notice that protection scope of the present invention should by any restriction of these examples.
Embodiment 1
A kind of aprepitant oral drugs tablet, formula is as follows:
Aprepitant and Hydroxypropyl Methyl Cellulose Phthalate are dissolved in dehydrated alcohol, drying under reduced pressure, dry thing are crossed 150 mesh sieves and obtains solid dispersion, for subsequent use;
(2) component C is crossed 150 mesh sieves to component F, for subsequent use;
(3) take the solid dispersion after sieving, add lactose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate wherein successively, mix homogeneously, be pressed into tablet.
Embodiment 2:
A kind of aprepitant oral drugs tablet, formula is as follows:
Aprepitant and Hydroxypropyl methyl cellulose phtalate are dissolved in dehydrated alcohol, drying under reduced pressure, dry thing are crossed 150 mesh sieves and obtains solid dispersion, for subsequent use;
(2) component C is crossed 150 mesh sieves to component F, for subsequent use;
(3) take the solid dispersion after sieving, add lactose, crospovidone, Talcum and magnesium stearate wherein successively, mix homogeneously, be pressed into tablet.
Embodiment 3:
A kind of aprepitant oral drug capsule, formula is as follows:
Aprepitant and Hydroxypropyl methyl cellulose phtalate are dissolved in dehydrated alcohol, drying under reduced pressure, dry thing are crossed 150 mesh sieves and obtains solid dispersion, for subsequent use;
(2) component C is crossed 150 mesh sieves to component F, for subsequent use;
(3) take the solid dispersion after sieving, add microcrystalline Cellulose, low-substituted hydroxypropyl cellulose and magnesium stearate wherein successively, mix homogeneously, load HPMC capsule shells.
Embodiment 4:
A kind of aprepitant oral drug capsule, formula is as follows:
Aprepitant and Hydroxypropyl Methyl Cellulose Phthalate are dissolved in dehydrated alcohol, drying under reduced pressure, dry thing are crossed 150 mesh sieves and obtains solid dispersion, for subsequent use;
(2) component C is crossed 150 mesh sieves to component F, for subsequent use;
(3) take the solid dispersion after sieving, add microcrystalline Cellulose, low-substituted hydroxypropyl cellulose and magnesium stearate wherein successively, mix homogeneously, load HPMC capsule shells.
Adopt the preparation of embodiment 1-4 and activated feedstock medicine aprepitant to carry out bioavailability experiment, utilize beasle dog to absorb crossing research methodology and test, be specially:
Selection body weight is 10-11kg, the age is 3-5 year and the healthy male beagle dogs (N=3) not being exposed to any medicine in nearest 3 months carries out Absorption Study.For empty stomach condition, make dog fasted overnight (not limiting water), then the preparation in 1 embodiment 1-3 (1.78mg/kg) is given via gavage, or particle diameter is the aprepitant crude drug powder of 100 ~ 500nm, then give 100mL water, and continue fasting 4 hours.From the beginning venous puncture blood is put in predetermined time.Suitably process is carried out with except deproteinize and interfering material to plasma sample, then adopts ABSciex4000QtrapLC/MS/MS to analyze.For fed condition, dog is allowed to take food after taking preparation 30min.Every other condition keeps identical.
Fig. 1 is the stripping schematic diagram of aprepitant preparation in biorelevant media (paddle method, 37 DEG C, the relevant dissolution medium of 500ml biology, 50 revs/min, HPLC mensuration).Passable from Fig. 1, adopt preparation of the present invention in biology is correlated with dissolution medium, have excellent result of extraction, and directly adopt crude drug aprepitant powder almost cannot stripping.As calculated, adopt preparation area under curve of the present invention to be 6412-8464nghr/mL, there is excellent bioavailability.
Fig. 2 is that aprepitant is at the representational plasma concentration schematic diagram of beasle dog.As can be seen from the figure, the active agent concentration of embodiment 1-3 can reach peak value in 3-4 hour, blood concentration peak value is between 1282-1458ng/mL, and the beasle dog directly taking crude drug aprepitant powder then cannot detect the concentration of aprepitant in its blood.Obviously, pharmaceutical preparation of the present invention can rapid solution, absorb by organism.
In sum, the preparation exhibits of the application goes out excellent dissolution and bioavailability, has significant value promotion relative to general acceptable commercial product, and has the stability of height.
The above embodiment only have expressed embodiments of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (7)
1. an aprepitant oral drug preparation, is characterized in that, comprises following component:
Component A: aprepitant 15-25wt%
Component B: Hydroxypropyl methyl cellulose phtalate and/or Hydroxypropyl Methyl Cellulose Phthalate 45-75wt%
Component C: microcrystalline Cellulose, lactose and/or mannitol 10-25wt%
Component D: low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose and/or crospovidone 2-8wt%
Component E: silicon dioxide and/or Talcum 0-2wt%
Component F: magnesium stearate 0-2wt%.
2. a kind of aprepitant oral drug preparation according to claim 1, it is characterized in that, said preparation comprises following component:
Component A: aprepitant 18-23wt%
Component B: Hydroxypropyl methyl cellulose phtalate and/or Hydroxypropyl Methyl Cellulose Phthalate 60-70wt%
Component C: microcrystalline Cellulose, lactose and/or mannitol 11-20wt%
Component D: low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose and/or crospovidone 3-6wt%
Component E: silicon dioxide and/or Talcum 0.5-2wt%
Component F: magnesium stearate 1-2wt%.
3. a kind of aprepitant oral drug preparation according to claim 1, is characterized in that, component A: component C: the weight ratio of component F is 1:(1-1.1): (0.025-0.055).
4. a kind of aprepitant oral drug preparation according to claim 1, is characterized in that, described preparation is capsule or tablet.
5. a kind of aprepitant oral drug preparation according to claim 1, it is characterized in that, in described preparation, per unit dosage contains the aprepitant of 80-85mg.
6. a kind of aprepitant oral drug preparation according to claim 1, is characterized in that, the capsule shells that the capsule shells that described preparation uses is gelatin and/or hydroxypropyl emthylcellulose.
7. the preparation method of a kind of aprepitant oral drug preparation according to any one of claim 1-6, is characterized in that, comprise the steps:
(1) component A and component B is dissolved in dehydrated alcohol, drying under reduced pressure, dry thing is crossed 150 mesh sieves and obtains solid dispersion, for subsequent use;
(2) component C is crossed 150 mesh sieves to component F, for subsequent use;
(3) take the solid dispersion after sieving, add component C successively wherein to component F, mix homogeneously, tabletting or encapsulation capsule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610111912.5A CN105534987A (en) | 2016-02-29 | 2016-02-29 | Aprepitant oral pharmaceutical preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610111912.5A CN105534987A (en) | 2016-02-29 | 2016-02-29 | Aprepitant oral pharmaceutical preparation |
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| Publication Number | Publication Date |
|---|---|
| CN105534987A true CN105534987A (en) | 2016-05-04 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610111912.5A Pending CN105534987A (en) | 2016-02-29 | 2016-02-29 | Aprepitant oral pharmaceutical preparation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108030924A (en) * | 2017-12-29 | 2018-05-15 | 成都百裕制药股份有限公司 | A kind of preparation method of high stability Aprepitant composition |
| CN108324720A (en) * | 2018-06-06 | 2018-07-27 | 南京海融制药有限公司 | Aprepitant pharmaceutical composition and the method for improving its bioavilability |
| JP2019073445A (en) * | 2017-10-12 | 2019-05-16 | 日本化薬株式会社 | Pharmaceutical composition containing aprepitant as active ingredient |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008104512A2 (en) * | 2007-02-27 | 2008-09-04 | Sandoz Ag | Novel polymorphs of aprepitant and processes for preparation |
-
2016
- 2016-02-29 CN CN201610111912.5A patent/CN105534987A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008104512A2 (en) * | 2007-02-27 | 2008-09-04 | Sandoz Ag | Novel polymorphs of aprepitant and processes for preparation |
Non-Patent Citations (1)
| Title |
|---|
| 王如意等: "醋酸羟丙甲纤维素琥珀酸酯在制备固体分散体中的应用", 《中国医药工业杂志》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2019073445A (en) * | 2017-10-12 | 2019-05-16 | 日本化薬株式会社 | Pharmaceutical composition containing aprepitant as active ingredient |
| CN108030924A (en) * | 2017-12-29 | 2018-05-15 | 成都百裕制药股份有限公司 | A kind of preparation method of high stability Aprepitant composition |
| CN108030924B (en) * | 2017-12-29 | 2021-01-05 | 成都百裕制药股份有限公司 | Preparation method of high-stability aprepitant composition |
| CN108324720A (en) * | 2018-06-06 | 2018-07-27 | 南京海融制药有限公司 | Aprepitant pharmaceutical composition and the method for improving its bioavilability |
| CN108324720B (en) * | 2018-06-06 | 2020-06-30 | 南京海融医药科技股份有限公司 | Aprepitant pharmaceutical composition and method for improving bioavailability thereof |
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Application publication date: 20160504 |