CN112891306A - O/W type entecavir microemulsion oral liquid and preparation method thereof - Google Patents
O/W type entecavir microemulsion oral liquid and preparation method thereof Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
- A61K47/44—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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- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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Abstract
The invention discloses O/W type entecavir microemulsion oral liquid, which comprises the following components in 100 mL: 0.0025-0.005 g of entecavir, 10-25 g of oil phase solvent, 1-3 g of emulsifier, 0.5-2 g of auxiliary emulsion, 0.05-0.2 g of preservative, 0.1-0.3 g of flavoring agent, 0.01-0.1 g of aromatic and the balance of water; the emulsifier is caprylic capric glyceride, and the auxiliary emulsion is beeswax. The O/W type microemulsion oral liquid has stable property, good uniformity, difficult occurrence of the problems of emulsion breaking, layering, flocculation and the like, good taste, high medicine taking compliance of patients and obviously improved oral bioavailability of the entecavir.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to O/W type entecavir microemulsion oral liquid and a preparation method thereof.
Background
Entecavir is known by the chemical name 2-amino-9- [ (1S,3S,4S) -4-hydroxy-3-hydroxymethyl-2-methylenepentyl]-1, 9-hydro-6-H-purin-6-one-hydrate with molecular formula C12H15N5O3·H2And O. Entecavir is a new generation guanine nucleoside analogue oral medicine for treating hepatitis B virus infection, is mainly used for treating adult chronic hepatitis B accompanied by virus replication activity and continuous increase of serum transaminase or active pathological change of liver histology, is a nucleoside analogue which has the strongest virus reduction speed and the lowest variation probability at present, and is considered to have good clinical application prospect in medicines for treating chronic hepatitis B.
The oral liquid preparation has obvious advantages clinically, and can well solve the problems of difficult sub-dosage, poor medicine taking compliance and the like, especially for special crowds such as children, old patients and the like. At present, only an entecavir oral solution preparation belongs to an oral liquid preparation in the preparation of entecavir on the market, and water is generally used as a solvent. However, because entecavir has poor water solubility, the solubility is only about 2.4mg/mL, resulting in low bioavailability of entecavir.
Disclosure of Invention
In order to solve the defects in the prior art, the invention aims to provide O/W type entecavir microemulsion oral liquid and a preparation method thereof, so as to improve the bioavailability of entecavir.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
an O/W type entecavir microemulsion oral liquid, which is calculated by 100mL, comprises the following components:
the emulsifier is caprylic capric glyceride, and the auxiliary emulsion is beeswax.
The invention adopts the caprylic capric glyceride as the emulsifier and the beeswax as the auxiliary emulsion, and the two are complementary to each other, so that the stable O/W type microemulsion can be prepared, the solubility, the dissolution rate and the permeability of gastrointestinal mucosa of the entecavir are obviously improved, and the oral bioavailability of the entecavir is effectively improved.
The caprylic capric acid glyceride is a transparent low-viscosity liquid, is colorless, tasteless and nontoxic, has light smell, mellow taste, is not easy to oxidize, and has good chemical stability; the carbon chain is short, the oil-water composite material has good intermiscibility with solvents, grease and additives in the formula, and has good intersolubility and dissolubility between water and oil. In addition, the caprylic capric glyceride can be rapidly metabolized in vivo, is easy to be digested and absorbed by human body, does not accumulate, does not increase weight, and is more beneficial to human health.
The beeswax is a natural fatty substance secreted by 4 pairs of wax glands on the abdomen of worker bees with proper age in a bee colony, can prevent the entecavir from being oxidized and hydrolyzed, can cover the bitter taste of the entecavir and the unpleasant odor of other components, improves the mouthfeel, improves the medicine taking compliance of patients, and reduces the adding amount of a flavoring agent and an aromatic in a formula system.
Preferably, in the O/W type entecavir microemulsion oral liquid, the weight ratio of the emulsifier: and (1-3) the auxiliary emulsion is 1. In the formula of the invention, when the emulsifier and the auxiliary emulsion are combined and used according to the weight ratio, the microemulsion oral liquid with better uniformity and stability can be prepared.
More preferably, in the O/W type entecavir microemulsion oral liquid, the weight ratio of the emulsifier: the auxiliary emulsion is 2: 1. In the formula of the invention, when the emulsifier and the co-emulsion are used in combination according to the weight ratio, the uniformity and the stability of the microemulsion oral liquid are better.
Preferably, the oil phase solvent comprises at least one of corn oil, oleic acid, soybean oil, palmitic acid.
Preferably, the preservative comprises at least one of methylparaben, ethylparaben, propylparaben, and butylparaben. The hydroxybenzoic acid ester preservative is an excellent preservative, has no toxicity, no odor and stable chemical properties. According to the invention, a small amount of the preservative is added into the microemulsion oral liquid according to the formula, so that the breeding and propagation of microorganisms can be effectively inhibited, and the product safety is improved.
More preferably, the preservative is butyl paraben. In the formula of the invention, when the butyl p-hydroxybenzoate is added, the microemulsion oral liquid has the strongest antibacterial effect.
Preferably, the flavoring agent comprises at least one of stevioside, sucralose, acesulfame potassium, and sorbitol.
Preferably, the aromatic includes at least one of mint essence, pineapple essence, lemon essence, sweet orange essence, banana essence, and peach essence.
The invention also provides a preparation method of the O/W type entecavir microemulsion oral liquid, which comprises the following steps:
(1) adding entecavir into the oil phase solvent, stirring and dissolving;
(2) adding an emulsifier, an auxiliary emulsifier and a preservative into the solution obtained in the step (1), uniformly stirring, then adding 20-30% of water according to the prescription amount, and stirring for 3-5 min at a speed of 10000-20000 r/min to form primary emulsion;
(3) and (3) pouring the primary emulsion obtained in the step (2) into a homogenizer, adding a flavoring agent, an aromatic and the balance of water, homogenizing and dispersing for 10-15 min at 10000-20000 r/min to form a stable O/W type emulsion, filling and sealing, and sterilizing to obtain the O/W type entecavir micro-emulsion oral liquid.
Compared with the prior art, the invention has the beneficial effects that: the O/W microemulsion oral liquid prepared by the formula and the method has stable property, good uniformity, difficult occurrence of problems of emulsion breaking, layering, flocculation and the like, good taste, high medicine taking compliance of patients and obviously improved oral bioavailability of entecavir.
Detailed Description
The technical solutions of the present invention will be further described with reference to the following embodiments, and it should be apparent that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The starting materials used in the examples are all commercially available.
Example 1
An O/W type entecavir microemulsion oral liquid, which is calculated by 100mL, comprises the following components:
the emulsifier is caprylic capric glyceride, and the auxiliary emulsion is beeswax.
The preparation method of the O/W type entecavir microemulsion oral liquid comprises the following steps:
(1) adding entecavir into soybean oil, stirring and dissolving;
(2) adding an emulsifier, an auxiliary emulsifier and butyl p-hydroxybenzoate into the solution obtained in the step (1), uniformly stirring, then adding 20-30% of water according to the prescription amount, and stirring at 10000r/min for 5min to form primary emulsion;
(3) and (3) pouring the primary emulsion obtained in the step (2) into a homogenizer, adding sucralose, lemon essence and the balance of water, homogenizing and dispersing for 10min at 20000r/min to form a stable O/W type emulsion, encapsulating, and sterilizing to obtain the O/W type entecavir micro-emulsion oral liquid.
Example 2
An O/W type entecavir microemulsion oral liquid, which is calculated by 100mL, comprises the following components:
the emulsifier is caprylic capric glyceride, and the auxiliary emulsion is beeswax.
The preparation method of the O/W type entecavir microemulsion oral liquid comprises the following steps:
(1) adding entecavir into corn oil, stirring and dissolving;
(2) adding an emulsifier, an auxiliary emulsifier and butyl p-hydroxybenzoate into the solution obtained in the step (1), uniformly stirring, then adding 20-30% of water according to the prescription amount, and stirring for 3min at 20000r/min to form primary emulsion;
(3) and (3) pouring the primary emulsion obtained in the step (2) into a homogenizer, adding acesulfame potassium, stevioside, orange essence and the balance of water, homogenizing and dispersing for 15min at 10000r/min to form a stable O/W type emulsion, filling and sealing, and sterilizing to obtain the O/W type entecavir micro-emulsion oral liquid.
Example 3
An O/W type entecavir micro-emulsion oral liquid is different from the embodiment 1 only in the addition amount of an emulsifying agent and an auxiliary emulsion, in the embodiment, the addition amount of an emulsifying agent, namely caprylic/capric glyceride is 1.5g, and the addition amount of auxiliary emulsion, namely beeswax is 1.5 g.
Example 4
An O/W type entecavir micro-emulsion oral liquid is different from the embodiment 1 only in the addition amount of an emulsifying agent and an auxiliary emulsion, in the embodiment, the addition amount of the emulsifying agent, namely the caprylic/capric glyceride is 2.25g, and the addition amount of the auxiliary emulsion, namely the beeswax is 0.75 g.
Example 5
An O/W type entecavir micro-emulsion oral liquid is different from the embodiment 1 only in the addition amount of an emulsifying agent and an auxiliary emulsion, in the embodiment, the addition amount of an emulsifying agent, namely caprylic/capric glyceride is 1g, and the addition amount of auxiliary emulsion, namely beeswax is 2 g.
Example 6
An O/W type entecavir micro-emulsion oral liquid is different from the embodiment 1 only in the addition amount of an emulsifying agent and an auxiliary emulsion, in the embodiment, the addition amount of an emulsifying agent, namely caprylic capric glyceride is 2.4g, and the addition amount of auxiliary emulsion, namely beeswax is 0.6 g.
Comparative example 1
Comparative example 1 differs from example 1 only in the amount of emulsifier and co-emulsion added. In comparative example 1, the addition amount of emulsifier caprylic capric acid glyceride was 3g, and the addition amount of auxiliary emulsifier beeswax was 0 g.
Comparative example 2
Comparative example 2 differs from example 1 only in the amount of emulsifier and co-emulsion added. In comparative example 2, the addition amount of emulsifier caprylic capric acid glyceride was 0g, and the addition amount of auxiliary emulsifier beeswax was 3 g.
First, particle size distribution uniformity and stability investigation
The uniformity and stability of the particle size distribution of the products prepared in examples 1-6 and comparative examples 1-2 were examined, and the average particle size was characterized using a Malvern dynamic light scattering laser particle size analyzer, the results of which are shown in the following table.
| Sample (I) | Average particle diameter (nm) after standing for 0 day | Average particle size (nm) after standing for 1 month |
| Example 1 | 92.31 | 92.36 |
| Example 2 | 160.42 | 161.30 |
| Example 3 | 115.18 | 115.24 |
| Example 4 | 109.76 | 109.82 |
| Example 5 | 270.91 | 267.15 |
| Example 6 | 285.73 | 291.06 |
| Comparative example 1 | 3019 | 7895 |
| Comparative example 2 | 4165 | 9813 |
From the results in the table, the microemulsion oral liquid prepared by the formula of the invention in the examples 1-6 has the particle size below 300nm, uniform particle size distribution, no obvious change in average particle size after being placed for 1 month, good stability, no delamination, demulsification and the like. Among them, comparing example 1 with examples 3 to 6, it can be seen that example 1 has the smallest average particle size, the most uniform particle size distribution, and better stability; next, example 3 and example 4; the average particle diameters of examples 5 and 6 were significantly larger than those of examples 1 and 3 to 4, and the uniformity and stability of the particle diameter distribution were also inferior to those of examples 1 and 3 to 4. The microemulsion oral liquid has the advantages that the proportion of the caprylic-capric glyceride to the beeswax in the formula of the microemulsion oral liquid influences the uniformity and the stability of the microemulsion oral liquid, and the microemulsion oral liquid with better uniformity and stability can be prepared when the weight ratio of the caprylic-capric glyceride to the beeswax is (1-3): 1.
As can be seen from the table above, the products prepared in comparative example 1 and comparative example 2 have larger particle size, the average particle size is above 3000nm, the particle size distribution is uneven, and after the products are placed for 1 month, the average particle size is increased to above 7500nm, which indicates that the products have agglomeration phenomenon and poor stability. Therefore, the stable O/W type microemulsion can be prepared only by simultaneously adding the caprylic-capric glyceride and the beeswax in the formula.
Second, bioavailability test
By adopting a self-control method, 90 rats are randomly divided into 9 groups, 10 rats are respectively numbered as examples 1-6 groups, comparative examples 1-2 groups and a control group. The products prepared in the examples 1-6 and the comparative examples 1-2 are orally taken in the groups 1-6 and the comparative examples 1-2 respectively, the commercial tablet 'boldetermining' is orally taken in the control group, the dosage is 0.5mg/kg of single-dose intragastric administration, and the change condition of the concentration of the entecavir in the plasma of rats along with time is measured. Plasma entecavir concentrations (in ng/mL) were recorded at 10min, 20min, 30min, 40min, 60min, and 1440min after administration to rats, respectively, and the results are shown in the following table.
| Sample (I) | 10min | 20min | 30min | 40min | 60min | 1440min |
| EXAMPLE 1 group | 50.7 | 133.6 | 102.0 | 90.6 | 74.3 | 0.5 |
| EXAMPLE 2 group | 36.4 | 90.1 | 113.6 | 103.9 | 91.2 | 0.9 |
| EXAMPLE 3 group | 48.0 | 120.4 | 99.1 | 94.0 | 81.8 | 0.7 |
| EXAMPLE 4 group | 46.5 | 122.5 | 110.3 | 92.5 | 78.6 | 0.6 |
| EXAMPLE 5 group | 28.1 | 81.1 | 116.5 | 103.7 | 92.2 | 1.1 |
| EXAMPLE 6 group | 27.6 | 80.5 | 111.2 | 103.8 | 93.4 | 1.2 |
| Comparative example 1 group | 17.3 | 44.7 | 83.3 | 105.4 | 96.1 | 1.1 |
| Comparative example 2 group | 15.8 | 41.9 | 80.5 | 103.8 | 97.6 | 1.4 |
| Control group | 7.5 | 28.3 | 53.7 | 69.5 | 98.7 | 1.3 |
As can be seen from the results in the table, the products of the groups 1-6 have higher bioavailability, and the concentration of entecavir 1 in rat plasma after administration for 10min is obviously higher. In addition, the peak reaching time of the product in example 1 and examples 3 to 4 is obviously shifted, the highest blood concentration is obviously increased, the product can be quickly absorbed in a living body, and the effect of the product in example 1 is the best.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (9)
1. The O/W type entecavir micro-emulsion oral liquid is characterized in that the O/W type entecavir micro-emulsion oral liquid comprises the following components by 100 mL:
the emulsifier is caprylic capric glyceride, and the auxiliary emulsion is beeswax.
2. The O/W type entecavir micro-emulsion oral liquid of claim 1, wherein in the O/W type entecavir micro-emulsion oral liquid, the weight ratio of the emulsifier: and (1-3) the auxiliary emulsion is 1.
3. The O/W type entecavir micro-emulsion oral liquid of claim 1, wherein in the O/W type entecavir micro-emulsion oral liquid, the weight ratio of the emulsifier: the auxiliary emulsion is 2: 1.
4. The O/W entecavir microemulsion oral liquid of claim 1 wherein the oil phase solvent comprises at least one of corn oil, oleic acid, soybean oil, palmitic acid.
5. The O/W entecavir microemulsion oral liquid of claim 1 wherein the preservative comprises at least one of methylparaben, ethylparaben, propylparaben, and butylparaben.
6. The O/W entecavir microemulsion oral liquid of claim 5 wherein the preservative is butylparaben.
7. The O/W entecavir microemulsion oral liquid of claim 1 wherein the flavoring agent comprises at least one of stevia, sucralose, acesulfame k, sorbitol.
8. The O/W entecavir microemulsion oral liquid of claim 1 wherein the flavoring agent comprises at least one of mint, pineapple, lemon, sweet orange, banana, and peach flavors.
9. The preparation method of the O/W type entecavir micro-emulsion oral liquid according to any one of claims 1 to 8, characterized by comprising the following steps:
(1) adding entecavir into the oil phase solvent, stirring and dissolving;
(2) adding an emulsifier, an auxiliary emulsifier and a preservative into the solution obtained in the step (1), uniformly stirring, then adding 20-30% of water according to the prescription amount, and stirring for 3-5 min at a speed of 10000-20000 r/min to form primary emulsion;
(3) and (3) pouring the primary emulsion obtained in the step (2) into a homogenizer, adding a flavoring agent, an aromatic and the balance of water, homogenizing and dispersing for 10-15 min at 10000-20000 r/min to form a stable O/W type emulsion, filling and sealing, and sterilizing to obtain the O/W type entecavir micro-emulsion oral liquid.
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2021
- 2021-03-24 CN CN202110315499.5A patent/CN112891306A/en active Pending
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Application publication date: 20210604 |