CN107184549B - Nintedanib self-microemulsion preparation, soft capsule prepared from same and preparation method of soft capsule - Google Patents
Nintedanib self-microemulsion preparation, soft capsule prepared from same and preparation method of soft capsule Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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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
- A61K9/4858—Organic compounds
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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
Abstract
The invention provides a Nintedanib self-microemulsion preparation, a soft capsule prepared from the same and a preparation method of the Nintedanib self-microemulsion preparation, wherein the concentration of the Nintedanib in the Nintedanib self-microemulsion preparation is 2-3% by mass percent; the proportion of the oil phase in the self-microemulsion preparation of the nintedanib is 10-30% (w/w); the proportion of the emulsifier in the self-microemulsion preparation of the nintedanib is 20-40% (w/w); the proportion of the auxiliary emulsifier in the self-microemulsion preparation of the nintedanib is 20-60% (w/w); the proportion of the stabilizer in the self-microemulsion preparation of the nintedanib is 0-3% (w/w). The invention prepares the prepared Nintedanib self-microemulsion preparation into the Nintedanib self-microemulsion soft capsule by a self-microemulsion technology, the Nintedanib self-microemulsion preparation can be quickly emulsified when meeting the aqueous environment of the gastrointestinal tract, so that the irritation generated after the medicament contacts the gastrointestinal tract for a long time is reduced, and the self-microemulsion medicament carrying system can improve the dissolution rate of the medicament, improve the speed and the degree of medicament absorption and further improve the bioavailability of the medicament.
Description
Technical Field
The invention belongs to the field of research of pharmaceutical preparations, and particularly relates to a nintedanib self-microemulsion preparation, a soft capsule prepared from the nintedanib self-microemulsion preparation and a preparation method of the soft capsule.
Background
The 6-month-old brigrove invager company announced that the application for marketing approval of the nidanib to treat Idiopathic Pulmonary Fibrosis (IPF) was validated by the European Medicines Agency (EMA), and incorporated into the accelerated approval list. On 15/10/2014, the U.S. food and drug administration FDA approved new oral drugs of nedanib ethanesulfonate (trade name: Ofev) for the treatment of Idiopathic Pulmonary Fibrosis (IPF).
Nintedanib is chemically (3Z) -2, 3-dihydro-3- [ [ [4- [ methyl [2- (4-methyl-1-chatuzyl) phthalide ] amino ] phenyl ] amino ] benzylidene ] -2-oxo-1H-indole-6-carboxylic acid methyl acetate, and has the structural formula:
based on the biopharmaceutical classification system, bulk drugs can be classified into four major classes according to their solubility and permeability differences. Low solubility, high permeability drugs belong to class II of the biopharmaceutical classification, with the rate-limiting step in absorption being the low dissolution rate of the drug. Dosage forms play a decisive role in the absorption of such drugs in the gastrointestinal tract, and traditional tablets have difficulty in improving the bioavailability of such drugs, and proper dosage forms are the key to the successful development of such drug products. (Lvjinfan et al, research on administration strategies of poorly soluble drugs, world clinical drugs, 2009,30(1): 41-45).
Micro Emulsions (ME), also known as nanoemulsions (nanoemulsions), are a stable colloidal dispersion between conventional emulsions and micellar solutions. The microemulsion has droplet size of 10-100nm, and can increase solubility of medicine and promote absorption of medicine in gastrointestinal tract.
Self-microemulsifying formulations, also known as self-microemulsifying drug delivery systems (SMEDDS). After oral administration, the self-microemulsion preparation encounters gastric juice in gastrointestinal tract, self-microemulsifies under gastrointestinal peristalsis to form o/w type drug-loaded microemulsion, the particle size of the o/w type drug-loaded microemulsion is consistent with that of the microemulsion with the same composition, and the bioavailability of the drug is further improved. Self-microemulsion formulations typically include an oil phase, a surfactant, a co-surfactant, and a drug. Compared with microemulsion, the SMEDDS has improved stability, can meet the requirement of long-term storage, and can be directly filled into traditional drug delivery systems such as soft capsules or hard capsules.
CN101091696A A self-microemulsion preparation of oridonin is prepared by using oil phase, surfactant, cosurfactant and other adjuvants. CN101130059A uses anhydrous alcohol, propylene glycol, span-80, polyoxyethylene hydrogenated castor oil RH40, medium-chain fatty acid glycerol and other auxiliary materials to prepare the self-microemulsifying soft capsule of the surround essence A. CN101019833A uses oil phase, surfactant and cosurfactant to prepare the non-aqueous microemulsion of puerarin, propolis, kurarinone and the like. CN100536921C discloses a self-emulsifying drug delivery system of yellow-answer smoothie, glycyrrhizic acid and silymarin, and the auxiliary materials comprise an oil phase, a surfactant, a cosurfactant, a cationic surfactant and a high molecular polymer. CN101596177A (2009.12.9) discloses a coenzyme Q10 self-emulsifying composition, and auxiliary materials comprise phospholipid, a surfactant, a cosolvent and medium-chain fatty acid glycerol. In Eihua et al, puerarin is firstly prepared into self-microemulsion by utilizing an oil phase (peanut oil, castor oil, ethyl oleate and liquid paraffin), a surfactant and a cosurfactant, and then is adsorbed by a solid auxiliary material (the development of the puerarin solid self-microemulsion, a traditional Chinese medicine material, 2006, 29(8)834 and 838).
Disclosure of Invention
The invention aims to provide a nintedanib self-microemulsion preparation, a soft capsule prepared from the nintedanib self-microemulsion preparation and a preparation method of the nintedanib self-microemulsion soft capsule.
The technical scheme of the invention is as follows: a Nintedanib self-microemulsion preparation is a liquid self-microemulsion soft capsule preparation.
The self-microemulsion preparation of the nintedanib comprises nintedanib, an oil phase, an emulsifier, an auxiliary emulsifier and a stabilizer; the concentration of the nintedanib in the nintedanib self-microemulsion preparation is 2-3% by mass, preferably 2.5%; the proportion of the oil phase in the self-microemulsion preparation of the nintedanib is 10-30% (w/w); the proportion of the emulsifier in the self-microemulsion preparation of the nintedanib is 20-40% (w/w); the proportion of the auxiliary emulsifier in the self-microemulsion preparation of the nintedanib is 20-60% (w/w); the proportion of the stabilizer in the self-microemulsion preparation of the nintedanib is 0-3% (w/w).
Wherein the oil phase is one of propylene glycol monocaprylate (Capryol 90), castor oil, Medium Chain Triglyceride (MCT) or ethyl oleate;
the emulsifier is one or a mixture of more of caprylic/capric acid ester polyethylene glycol glyceride (LABRASOL), Tween 80(Tween 80), Tween 20(Tween 20), polyoxyethylene 35 castor oil (EL35), polyoxyethylene 40 hydrogenated castor oil (RH40), Span80 (Span80) or isopropyl myristate, and preferably one or a mixture of two.
The auxiliary emulsifier is one or a mixture of more of ethanol, Ethylene Glycol (EG), Propylene Glycol (PG), polyethylene glycol 400(PEG 400), Glycerol (GI) or polyethylene glycol 200(PEG200), and preferably one or a mixture of two of the ethanol, the Ethylene Glycol (EG), the Propylene Glycol (PG), the polyethylene glycol 400(PEG 400), the Glycerol (GI) or the polyethylene glycol 200(PEG 200).
The stabilizer is povidone K90(PVP K90).
A nintedanib self-microemulsion soft capsule prepared according to the nintedanib self-microemulsion preparation, comprising the nintedanib self-microemulsion preparation and a soft capsule shell; the self-microemulsion preparation of nintedanib is sealed in a soft capsule shell in a liquid form.
The preparation method of the self-microemulsion soft capsule comprises the steps of adding the nintedanib into an oil phase, an emulsifier or an auxiliary emulsifier for dissolving, then adding other raw materials for uniformly mixing to prepare the self-microemulsion preparation of the nintedanib, and filling the self-microemulsion preparation of the nintedanib into a soft capsule shell by adopting a conventional method to obtain the self-microemulsion soft capsule of the nintedanib. The method specifically comprises the following steps:
step (1) preparing the nintedanib, the oil phase, the emulsifier, the co-emulsifier and/or the stabilizer according to the following proportion of the prescription,
the concentration of the nintedanib in the nintedanib self-microemulsion preparation is 2-3% by mass percent,
the proportion of the oil phase in the Nintedanib self-microemulsion preparation is 10-30% by mass,
the proportion of the emulsifier in the Nintedanib self-microemulsion preparation is 20-40% by mass,
the auxiliary emulsifier accounts for 20 to 60 mass percent of the self-microemulsion preparation of the nintedanib,
the proportion of the stabilizer in the self-microemulsion preparation of the nintedanib is 0-3% by mass;
step (2) dissolving the formulated nintedanib in the co-emulsifier;
step (3) adding the emulsifier and the oil phase of the formula into the solution obtained in the step (2), and uniformly mixing;
if the formula comprises the stabilizer, adding the stabilizer into the solution obtained in the step (3), and dissolving and mixing uniformly to obtain the self-microemulsion preparation of the nintedanib;
and (5) filling the self-microemulsion preparation of the nintedanib obtained in the step (4) into a soft capsule shell to prepare the self-microemulsion soft capsule of the nintedanib.
Compared with the prior art, the invention has the beneficial effects that: the invention provides a preparation method of a Nintedanib self-microemulsion soft capsule, which utilizes the modern self-microemulsion technology to develop a Nintedanib self-microemulsion preparation and a reasonable production process flow, wherein the Nintedanib self-microemulsion preparation can be rapidly emulsified when meeting the aqueous environment of the gastrointestinal tract to form O/W type emulsion drops. The tiny oil drops can be quickly emptied from the stomach, so that the medicine is widely distributed in the whole gastrointestinal tract, thereby reducing the irritation generated after the medicine is contacted with the gastrointestinal tract for a long time. The self-microemulsion drug delivery system (SMEDDS) can improve the dissolution rate of the drug and the absorption rate and degree of the drug, thereby improving the bioavailability of the drug. The Nintedanib self-microemulsion soft capsule can make up the blank of Nintedanib medicaments in China to a certain extent, has important strategic significance for promoting the treatment of patients with idiopathic pulmonary fibrosis in China, improves the bioavailability of the Nintedanib prepared into the self-microemulsion, increases the drug effect of the Nintedanib in treating the idiopathic pulmonary fibrosis, and has very obvious social and civilian benefits in the implementation of the project.
Drawings
FIG. 1 is a ternary phase diagram of a blank self-microemulsion effective area that can be obtained by the present invention;
FIG. 2 is a ternary phase diagram of the proportion range of the self-microemulsion formula of Nintedanib with the Nintedanib concentration of 2.5% obtained by the method.
Detailed Description
The present invention will be described in further detail with reference to the following drawings and detailed description, but the scope of the present invention is not limited thereto.
Example 1
Propylene glycol monocaprylate (Capryol 90) is used as an oil phase, polyoxyethylene 40 hydrogenated castor oil (RH40) is used as an emulsifier, and Propylene Glycol (PG) is used as an auxiliary emulsifier. Mixing emulsifier and auxiliary emulsifier at weight ratio of 2:1, 1:2, mixing with oil phase at weight ratio of 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, 9:1, and mixing at 50 r.min-1Dropping into water preheated to 37 deg.C under stirring, and observing to obtain microemulsion. Recording the change condition and state of the mixing system with different proportions, limiting the proportion of the emulsifier to be 20-40%, the proportion of the co-emulsifier to be more than 20-60%, and the proportion of the oil phase to be 10-30%, drawing a ternary phase diagram according to the proportioning data, and selecting a blank self-microemulsion effective region and a Nintedanib self-microemulsion effective region, wherein the shaded part is shown in figure 1.
As can be seen from FIG. 2, the proportion of the components in the shaded area is selected to obtain a range of the proportion of the self-microemulsion formulation of Nintedanib with a concentration of 2.5%.
Filling the obtained self-microemulsion preparation of the nintedanib into a soft capsule shell to prepare the self-microemulsion soft capsule of the nintedanib.
Example 2
Nintedanib self-microemulsion preparation formula with concentration of 2% of nintedanib
Selecting raw materials according to the following proportion:
the preparation method comprises the following steps: dissolving the prescribed amount of nintedanib in the prescribed amount of PG, adding the prescribed amount of MCT and RH40, and mixing uniformly to obtain the self-microemulsion preparation of nintedanib.
The prepared self-microemulsion preparation of the nintedanib is colorless, uniform and transparent liquid. Taking the prepared Nintedanib self-microemulsion preparation, and diluting with water by 100 timesThe average particle diameter was 18.3nm when the particle diameter was measured. Taking 5ml of Nintedanib self-microemulsion preparation at 50 r.min-1Adding 10 times of 37 deg.C water under stirring, completely emulsifying in 1min to form transparent slightly blue O/W microemulsion at 50 r.min-1The mixture is kept stable for 8 hours under the stirring state, and no crystal is precipitated.
Example 3
Nintedanib self-microemulsion preparation formula with concentration of 2.5% of nintedanib
Selecting raw materials according to the following proportion:
the preparation method comprises the following steps: dissolving the prescribed amount of nintedanib in the prescribed amount of PG, adding the prescribed amount of MCT and RH40, and mixing uniformly to obtain the self-microemulsion preparation of nintedanib.
The prepared self-microemulsion preparation of the nintedanib is colorless, uniform and transparent liquid. Taking the prepared Nintedanib self-microemulsion preparation, diluting with water by 100 times, and measuring the particle size, wherein the average particle size is 18.1 nm. Taking 5ml of Nintedanib self-microemulsion preparation at 50 r.min-1Adding 10 times of 37 deg.C water under stirring, completely emulsifying in 1min to form transparent slightly blue O/W microemulsion at 50 r.min-1The mixture is kept stable for 8 hours under the stirring state, and no crystal is precipitated.
Example 4
Nintedanib self-microemulsion preparation formula with concentration of 2.9% of nintedanib
Selecting raw materials according to the following proportion:
the preparation method comprises the following steps: dissolving the prescribed amount of nintedanib in the prescribed amount of PG, adding the prescribed amount of MCT and RH40, uniformly mixing, adding the prescribed amount of PVP K90, and uniformly mixing after dissolving to obtain the self-microemulsion preparation of nintedanib.
Prepared nylonThe danibu self-microemulsion preparation is a colorless, uniform and transparent liquid. Taking the prepared Nintedanib self-microemulsion preparation, diluting with water by 100 times, and measuring the particle size, wherein the average particle size is 23.1 nm. Taking 5ml of Nintedanib self-microemulsion preparation at 50 r.min-1Adding 10 times of 37 deg.C water under stirring, completely emulsifying in 1min to form transparent slightly blue O/W microemulsion at 50 r.min-1The mixture is kept stable for 8 hours under the stirring state, and no crystal is precipitated.
Example 5
Nintedanib self-microemulsion preparation formula with concentration of 2.5% of nintedanib
Selecting raw materials according to the following proportion:
the preparation method comprises the following steps: dissolving the prescribed amount of nintedanib in the prescribed amount of PEG400, adding the prescribed amount of EL, RH40 and MCT, and mixing uniformly to obtain the self-microemulsion preparation of nintedanib.
The prepared self-microemulsion preparation of the nintedanib is colorless, uniform and transparent liquid. Taking the prepared Nintedanib self-microemulsion preparation, diluting with water by 100 times, and measuring the particle size, wherein the average particle size is 20.8 nm. Taking 5ml of Nintedanib from microemulsion at 50 r.min-1Adding 10 times of 37 deg.C water under stirring, completely emulsifying in 1min to form transparent slightly blue O/W microemulsion at 50 r.min-1The mixture is kept stable for 8 hours under the stirring state, and no crystal is precipitated.
Example 6
Nintedanib self-microemulsion preparation formula with concentration of 2.5% of nintedanib
Selecting raw materials according to the following proportion:
the preparation method comprises the following steps: dissolving the formulated amount of nintedanib in the formulated amount of PEG400, adding the formulated amount of Tween 80, RH40 and MCT, and mixing uniformly to obtain the self-microemulsion preparation of nintedanib.
The prepared self-microemulsion preparation of the nintedanib is colorless, uniform and transparent liquid. Taking the prepared Nintedanib self-microemulsion preparation, diluting with water by 100 times, and measuring the particle size, wherein the average particle size is 22.1 nm. Taking 5ml of Nintedanib from microemulsion at 50 r.min-1Adding 10 times of 37 deg.C water under stirring, completely emulsifying in 1min to form transparent slightly blue O/W microemulsion at 50 r.min-1The mixture is kept stable for 8 hours under the stirring state, and no crystal is precipitated.
Example 7
Nintedanib self-microemulsion preparation formula with concentration of 2.5% of nintedanib
Selecting raw materials according to the following proportion:
the preparation method comprises the following steps: dissolving the nintedanib in the amount of the prescription into the PFG 400 and ethanol mixed coemulsifier, adding RH40, Tween 20 and caprylic/capric acid ester polyethylene glycol glyceride in the amount of the prescription, uniformly mixing, adding PVP K30 in the amount of the prescription, and uniformly mixing after dissolving to obtain the self-microemulsion preparation of the nintedanib.
The prepared self-microemulsion preparation of the nintedanib is colorless, uniform and transparent liquid. Taking the prepared Nintedanib self-microemulsion preparation, diluting with water by 100 times, and measuring the particle size, wherein the average particle size is 25.7 nm. Taking 5ml of Nintedanib self-microemulsion preparation at 50 r.min-1Adding 10 times of 37 deg.C water under stirring, completely emulsifying in 1min to form transparent slightly blue O/W microemulsion at 50 r.min-1The mixture is kept stable for 8 hours under the stirring state, and no crystal is precipitated.
Example 8
Nintedanib self-microemulsion preparation formula with concentration of 2.5% of nintedanib
Selecting raw materials according to the following proportion:
the preparation method comprises the following steps: dissolving the nintedanib in the PG, adding the castor oil and the isopropyl myristate, and mixing to obtain the self-microemulsion preparation of the nintedanib.
The prepared Nintedanib self-microemulsion preparation is a light yellow uniform transparent liquid. Taking the prepared Nintedanib self-microemulsion preparation, diluting with water by 100 times, and measuring the particle size, wherein the average particle size is 24.2 nm. Taking 5ml of Nintedanib self-microemulsion preparation at 50 r.min-1Adding 10 times of 37 deg.C water under stirring, completely emulsifying in 1min to form transparent slightly blue O/W microemulsion at 50 r.min-1The mixture is kept stable for 8 hours under the stirring state, and no crystal is precipitated.
Example 9
Nintedanib self-microemulsion preparation formula with concentration of 2.5% of nintedanib
Selecting raw materials according to the following proportion:
the preparation method comprises the following steps: dissolving the nintedanib in the EG in the prescription amount, adding the ethyl oleate and the RH40 in the prescription amount, and uniformly mixing to obtain the self-microemulsion preparation of the nintedanib.
The prepared self-microemulsion preparation of the nintedanib is colorless, uniform and transparent liquid. Taking the prepared Nintedanib self-microemulsion preparation, diluting with water by 100 times, and measuring the particle size, wherein the average particle size is 21.0 nm. Taking 5ml of Nintedanib self-microemulsion preparation at 50 r.min-1Adding 10 times of 37 deg.C water under stirring, completely emulsifying in 1min to form transparent slightly blue O/W microemulsion at 50 r.min-1The mixture is kept stable for 4 hours under the stirring state, and no crystal is precipitated.
Example 10
Nintedanib self-microemulsion preparation formula with concentration of 2.5% of nintedanib
Selecting raw materials according to the following proportion:
the preparation method comprises the following steps: dissolving the nintedanib in the formula amount into the PFG 200 and glycerol mixed coemulsifier, adding RH40, Tween 20 and MCT in the formula amount, uniformly mixing, adding PVP K30 in the formula amount, dissolving and uniformly mixing to obtain the self-microemulsion preparation of the nintedanib.
The prepared self-microemulsion preparation of the nintedanib is colorless, uniform and transparent liquid. Taking the prepared Nintedanib self-microemulsion preparation, diluting with water by 100 times, and measuring the particle size, wherein the average particle size is 20.9 nm. Taking 5ml of Nintedanib self-microemulsion preparation at 50 r.min-1Adding 10 times of 37 deg.C water under stirring, completely emulsifying in 1min to form transparent slightly blue O/W microemulsion at 50 r.min-1The mixture is kept stable for 8 hours under the stirring state, and no crystal is precipitated.
Example 11
Nintedanib self-microemulsion preparation formula with concentration of 2.5% of nintedanib
Selecting raw materials according to the following proportion:
the preparation method comprises the following steps: dissolving the prescribed amount of nintedanib in the prescribed amount of PEG400, adding the prescribed amount of MCT and RH40, uniformly mixing, adding the prescribed amount of PVP K90, and uniformly mixing after dissolving to obtain the self-microemulsion preparation of nintedanib.
The prepared self-microemulsion preparation of the nintedanib is colorless, uniform and transparent liquid. Taking the prepared Nintedanib self-microemulsion preparation, diluting with water by 100 times, and measuring the particle size, wherein the average particle size is 27.8 nm. Taking 5ml of Nintedanib self-microemulsion preparation at 50 r.min-1Adding 10 times of 37 deg.C water under stirring, completely emulsifying in 1min to form transparent slightly blue O/W microemulsion at 50 r.min-1The mixture is kept stable for 8 hours under the stirring state, and no crystal is precipitated.
It should be understood that although the present description has been described in terms of various embodiments, not every embodiment includes only a single embodiment, and such description is for clarity purposes only, and those skilled in the art will recognize that the embodiments described herein may be combined as suitable to form other embodiments, as will be appreciated by those skilled in the art.
The above-listed detailed description is only a specific description of a possible embodiment of the present invention, and they are not intended to limit the scope of the present invention, and equivalent embodiments or modifications made without departing from the technical spirit of the present invention should be included in the scope of the present invention.
Claims (4)
1. The self-microemulsion preparation of the nintedanib is characterized by comprising the nintedanib, an oil phase, an emulsifier, an auxiliary emulsifier and a stabilizer;
the concentration of the nintedanib in the nintedanib self-microemulsion preparation is 2-3% by mass percent;
the proportion of the oil phase in the Nintedanib self-microemulsion preparation is 10-30% by mass;
the proportion of the emulsifier in the Nintedanib self-microemulsion preparation is 20-40% by mass;
the auxiliary emulsifier accounts for 20-60% of the Nintedanib self-microemulsion preparation in percentage by mass;
the proportion of the stabilizer in the self-microemulsion preparation of the nintedanib is 0-3% by mass;
the emulsifier is one or a mixture of more of caprylic acid/caprate macrogol glyceride, tween 80, tween 20, polyoxyethylene 35 castor oil, polyethylene glycol 40 hydrogenated castor oil, span80 or isopropyl myristate;
the auxiliary emulsifier is one or a mixture of more of ethanol, ethylene glycol, propylene glycol, polyethylene glycol 400, glycerol or polyethylene glycol 200;
the oil phase is one of propylene glycol monocaprylate, castor oil, medium chain triglyceride or ethyl oleate;
dissolving the nintedanib in the co-emulsifier, adding the emulsifier and the oil phase, uniformly mixing, adding the stabilizer, and uniformly dissolving and mixing to obtain the nintedanib self-microemulsion preparation, wherein the nintedanib self-microemulsion preparation is used for treating pulmonary fibrosis.
2. The self-microemulsion of nintedanib according to claim 1, wherein the concentration of nintedanib in the self-microemulsion of nintedanib is 2.5% by weight.
3. The self-microemulsion soft capsule of nintedanib prepared from the self-microemulsion preparation of nintedanib according to claim 1, which comprises the self-microemulsion preparation of nintedanib and a soft capsule shell; the self-microemulsion preparation of nintedanib is sealed in a soft capsule shell in a liquid form.
4. The preparation method of the nintedanib self-microemulsion soft capsule according to claim 3, which comprises the following steps:
the step (1) is to prepare the nintedanib, the oil phase, the emulsifier, the co-emulsifier and/or the stabilizer according to the following proportion,
the concentration of the nintedanib in the nintedanib self-microemulsion preparation is 2-3% by mass percent,
the proportion of the oil phase in the Nintedanib self-microemulsion preparation is 10-30% by mass,
the proportion of the emulsifier in the Nintedanib self-microemulsion preparation is 20-40% by mass,
the auxiliary emulsifier accounts for 20 to 60 mass percent of the self-microemulsion preparation of the nintedanib,
the proportion of the stabilizer in the self-microemulsion preparation of the nintedanib is 0-3% by mass;
the emulsifier is one or a mixture of more of caprylic acid/caprate macrogol glyceride, tween 80, tween 20, polyoxyethylene 35 castor oil, polyethylene glycol 40 hydrogenated castor oil, span80 or isopropyl myristate;
the auxiliary emulsifier is one or a mixture of more of ethanol, ethylene glycol, propylene glycol, polyethylene glycol 400, glycerol or polyethylene glycol 200;
the oil phase is one of propylene glycol monocaprylate, castor oil, medium chain triglyceride or ethyl oleate;
step (2) dissolving the nintedanib in the coemulsifier;
step (3) adding the emulsifier and the oil phase into the solution obtained in the step (2), and uniformly mixing;
step (4) adding the stabilizer into the solution obtained in the step (3), and dissolving and mixing uniformly to obtain the self-microemulsion preparation of the nintedanib;
and (5) filling the self-microemulsion preparation of the nintedanib obtained in the step (4) into a soft capsule shell to prepare the self-microemulsion soft capsule of the nintedanib.
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| WO2019197961A1 (en) * | 2018-04-09 | 2019-10-17 | Intas Pharmaceuticals Ltd. | Pharmaceutical composition of nintedanib esylate |
| CN110441198A (en) * | 2018-05-03 | 2019-11-12 | 人福普克药业（武汉）有限公司 | A method of Nintedanib partial size in detection Nintedanib soft capsule |
| BR112021007214A2 (en) | 2018-10-15 | 2021-08-10 | Cipla Limited | pharmaceutical formulation |
| TW202222313A (en) * | 2020-12-02 | 2022-06-16 | 大陸商湖南慧澤生物醫藥科技有限公司 | Self-microemulsion composition of axitinib |
| CN112618490A (en) * | 2020-12-31 | 2021-04-09 | 苏州中化药品工业有限公司 | Itraconazole self-microemulsion preparation and preparation method thereof |
| CN114569573A (en) * | 2022-03-09 | 2022-06-03 | 重庆师范大学 | Coenzyme Q prepared by self-microemulsifying10Method for preparing vitamin E soft capsule |
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