CN101869569A - Ready-to-use entecavir composite - Google Patents
Ready-to-use entecavir composite Download PDFInfo
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- CN101869569A CN101869569A CN200910082230A CN200910082230A CN101869569A CN 101869569 A CN101869569 A CN 101869569A CN 200910082230 A CN200910082230 A CN 200910082230A CN 200910082230 A CN200910082230 A CN 200910082230A CN 101869569 A CN101869569 A CN 101869569A
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- entecavir
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Abstract
The invention discloses a low-dose ready-to-use entecavir composite, belonging to the pharmaceutical field. The low-dose ready-to-use entecavir composite is a liquid pharmaceutical composition containing entecavir; the pH value of the composite is 3-7; and the composite comprises the following components: a) 0.001%-20% (w/v) of entecavir in proper pharmaceutically acceptable solvent; b) 0.01%-10% (w/v) of sweetener; and c) 0.01%-5% (w/v) of buffering agent. The low-dose ready-to-use entecavir composite has the advantages of high palatability, good stability and easy quantitative method and taking way.
Description
Technical field
The present invention relates to a kind of low dosage ready-to-use entecavir preparation, more specifically say so Entecavir fluid composition and powder composition belong to pharmaceutical field.
Background technology
Entecavir,
Have following chemical constitution:
It is a kind of antiviral agent that treatment hepatitis B virus (HBV) infects that is used for clinically at present.
US5206244 discloses the purposes of Entecavir and its treatment hepatitis B virus, and effective antiviral dosage that Zahler discloses oral or parenteral is about 1.0 to the 50mg/kg body weight, and required dosage can give with proper spacing several times at one day.
The method of the synthetic Entecavir of improvement is disclosed among the WO98/09964.
US-2001-0033864 and WO01/64421 A1 disclose the low dosage Entecavir formulation, especially tablet and capsule.
CN03813287 discloses the composition of liquid medicine that contains Entecavir.
Entecavir itself has intensive bitterness, in the existing ready-to-use entecavir fluid composition production technology, used sugar alcohols sweeting agents such as the maltose alcohol of about 65% (w/v) or xylitol to cover Entecavir, pH with solution is limited between the 5-7 with the pH buffer agent, has added antiseptic and essence simultaneously.
Prior art has following limitation:
1, the active component Entecavir contains amino, contains the ketone group that free aldehyde radical maybe can produce the aldehyde ketone change in the chemical constitution of maltose alcohol, xylose alcohols sweeting agent, easily with the amino generation mailland reaction of Entecavir, and the effectiveness of reduction active component.This is reflected at easier generation under the solutions of weak acidity, therefore in order to guarantee the effectiveness of active component as far as possible, the pH of compositions must be controlled between the 5-7.
2, the sugariness of sugar alcohols such as maltose alcohol, xylitol sweeting agent is lower, in order to cover the bitterness of Entecavir as much as possible, must use in a large number, in the disclosed technology of CN03813287, the use amount of sweeting agent has reached 65%, the sweetener of so a large amount of sugar alcohols is unfavorable for the use to the responsive patient of sugar;
3, use a large amount of sweeteners to increase the viscosity of medicinal liquid greatly in the fluid composition, can produce phenomenons such as wall built-up when taking, get it filled when taking and bring very big inconvenience to the patient, also be unfavorable for when the patient takes medicine simultaneously accurately quantitative, low dosage can reach the medicine of expecting therapeutic effect for using very for this, and is very improper.
Summary of the invention
The objective of the invention is to, provide a kind of mouthfeel good and that sweetener content is low, steady in a long-term ready-to-use entecavir fluid composition and powder composition.
For achieving the above object, the present invention is by the following technical solutions:
Low dosage ready-to-use entecavir preparation, for containing the composition of liquid medicine of Entecavir, pH value is 3-7, comprises
A) concentration in suitable pharmacy acceptable solvent is the Entecavir of 0.001%-20%w/v;
B) concentration is the sweetener of 0.01%-10%w/v; With
C) concentration is the buffer agent of 0.01%-5%w/v.
The concentration of described Entecavir is 0.005%-5%w/v.
Described sweetener is selected from one or more in sucralose, aspartame and the steviosin, and its concentration is 0.01%-2%w/v.
Described buffer agent is selected from one or more in citrate buffer, phosphate buffer and the acetate buffer, and its concentration is 0.1%-3%w/v.
Described low dosage ready-to-use entecavir preparation further comprises at least a following component that is selected from: antiseptic, flavoring agent and pH regulator agent; Antiseptic is selected from one or more in oxybenzene ester series, benzoic acid series and the sorbic acid series, and concentration is 0.01%-2%w/v; Flavoring agent is selected from orange flavor or grape essence, and its concentration is 0.01% to 2%w/v.
Low dosage ready-to-use entecavir preparation, for containing the powder composition of Entecavir, pH value is 3-7, it comprises
A) account for the Entecavir of powder composition gross weight 0.001wt.%-20wt.%;
B) account for the sweetener of powder composition gross weight 0.01wt.%-10wt.%; With
C) account for the buffer agent of powder composition gross weight 1wt.%-20wt.%.
The 0.005wt.%-5wt.% of described entecavir powder composition gross weight.
Described sweetener is selected from one or more in sucralose, aspartame and the steviosin.
Described buffer agent is selected from one or more in citrate buffer, phosphate buffer and the acetate buffer.
Described low dosage ready-to-use entecavir preparation also comprises at least a following component that is selected from: antiseptic, flavoring agent and its combination in any; Antiseptic is selected from one or more in oxybenzene ester series, benzoic acid series and the sorbic acid series, and its content is that about 0.01wt.% is to 5wt.%; Flavoring agent is selected from orange flavor or grape essence, and content is that 0.001wt.% is to 2wt.%.
CN03813287 discloses the liquid preparation composition and the preparation method of instant low dosage Entecavir.In the disclosure, mention, owing to have a primary amine groups on the chemical constitution of Entecavir, thereby tend to easily to react with any sweetener that contains aldehyde and/or ketone group or flavoring agent and to influence its stability, this is reflected under the weak acid (pH 3 to 4) the most remarkable, and in 5 to 7 times minimums of pH.
The discovery that we are surprised, after replacing maltose alcohols sweeting agent with sweeting agents such as sucralose, aspartames, because sweeting agents such as sucralose itself do not contain aldehyde radical or interconvertible ketone group, can keep the stability of Entecavir in solution in than the pH scope of broad; And because the pH of ready to use solution can be chosen in the faintly acid scope (pH3-5), make medicinal liquid have sour-sweet taste, its taste is easier to be accepted by people; Sweeting agent changes into after sucralose or aspartame or the steviosin, use amount seldom just can reach the purpose of covering the Entecavir bitterness, the viscosity of prepared medicinal liquid is well below the viscosity of the medicinal liquid that contains a large amount of maltose alcohols, this takes out medicinal liquid easily when taking, and it is convenient and quantitative exactly, accurately quantitatively low dosage can reach the medicine of expecting therapeutic effect for using very, is even more important.Because the sweeting agent that uses among the present invention does not all have physiologically active, can give the responsive patient of sugar is used, increased the scope of application of this product greatly.
The purpose of this invention is to provide convenient a use and good to eat Entecavir instant composition of liquid medicine, be used for the treatment of the hepatitis B virus infection in adult patient or the pediatric patients (comprising sugared responsive patient).This composition of liquid medicine also contains at least a one or more the following annexing ingredients that are selected from: sweetener, antiseptic, flavoring agent, buffer agent, pH regulator agent.
In one embodiment of the invention, liquid entecavir composition is a kind of instant pharmaceutical composition, and entecavir is present in the liquid instant pharmaceutical composition with about 0.001% amount to about 10% (w/v).Preferably, the amount of Entecavir about 0.005% to about 5% (w/v) in the said composition, and most preferably, the Entecavir amount is about 0.005% to about 1% (w/v).
In order to offset the bitterness of Entecavir, make composition palatable, can in compositions, add sweetener and pH regulator agent, sweetener comprises sucralose, aspartame and steviosin and their combination in any, the amount of sweetener is about 0.01% to about 10% (w/v), the consumption of preferred sweetener is 0.01-2% (w/v), and most preferred sweetener consumption is 0.1-0.5% (w/v).
In order further to strengthen the palatability of entecavir composite of the present invention, can add flavoring agent, for example: orange flavor, grape essence.Flavoring agent accounts for the amount of compositions about 0.001% to about 2% (w/v), and preferably, the amount of flavoring agent is about 0.01% to about 0.5% (w/v).
Compositions of the present invention also can contain antiseptic. and suitable antiseptic comprises, for example: oxybenzene ester series, benzoic acid series, sorbic acid series or its combination in any. antiseptic accounts for the amount of compositions about 0.01% to about 2% (w/v), preferably, the total amount that exists of antiseptic is about 0.05% to about 0.5% (w/v).
Though with sweeting agents such as sucralose is that sweetener can make medicine keep stable in very wide pH value scope, but for combination of oral medication, the taste of a stable little acid is easier to be accepted by the people, comprise buffer agent with the about 3-7 of the pH value of keeping compositions, preferably the pH value of compositions about 4 to 5 is important.Suitable reducing includes but not limited to citrate buffer, phosphate buffer, acetate buffer or its combination in any, the consumption of buffer agent is about 0.01% to 5% (w/v), preferably, the amount of buffer agent in compositions is about 0.1% to about 3.0% (w/v).
In another embodiment of the present invention, the powder that liquid entecavir composition is formulated as fluid composition when using makes.When preparing, powder is mixed with the water of scheduled volume to form liquid entecavir composition with powder. using an advantage of powder is to keep the stability of powder in its shelf life, the convenient storage and transportation.Each component concentrations of powder composition of the present invention is by representing (Wt.%) based on the percentage by weight of powder composition gross weight.
The amount of antiviral agent entecavir powder composition is about 0.001% to about 20%, and preferably, the amount of Entecavir in powder composition is 0.005% to about 5.0%, more preferably from about 0.005% to about 1%.
In order to overcome the bitterness relevant with Entecavir, make compositions good to eat in use, can as above-mentioned liquid entecavir composition, in powder composition, add sweetener and comprise sucralose, aspartame, steviosin or its arbitrary composition.The amount of sweetener is about 0.001% to about 10% in the powder composition, and based on the weight of powder composition preferably, the amount that sweetener exists in compositions is about 0.01% to about 3%.
In order further to strengthen the palatability of powder composition of the present invention, can as above-mentioned liquid entecavir composition, in powder composition, add flavoring agent, for example orange flavor etc.The amount of flavoring agent can arrive about 2.0wt% for about 0.001wt% in the powder composition.
The antiseptic that the powder that is used to prepare the present composition also can contain as above-mentioned fluid composition sample of the present invention comprises being not limited to oxybenzene ester series benzoic acid series, sorbic acid series or its combination in any.The amount of the antiseptic in the powder composition is about 0.01% to about 5%.
For containing oral administration solution type powder composition, contain buffer agent to keep a metastable pH3-7, the preferred about 4-5 environment of pH is important, can use suitable reducing as above-mentioned liquid entecavir composition, these buffer agents comprise and are not limited to citrate buffer, phosphate buffer, acetate buffer or its any mixing.The amount of buffer agent is about 1% to about 20% in the powder composition, preferably, and its amount about 5% to about 10%.
The specific embodiment
Embodiment 1
Table 1 instant liquid entecavir composition (0.05mg/ml) composition
| Composition | Consumption (g/100ml) | Effect |
| Entecavir | ??0.005 | Active component |
| Sucralose | ??0.5 | Sweetener |
| Citric acid | ??0.5 | The pH buffer agent |
| Sodium citrate | ?0.3 | The pH buffer agent |
| Methyl parahydroxybenzoate | ?0.075 | Antiseptic |
| Propyl p-hydroxybenzoate | ?0.015 | Antiseptic |
| Orange flavor | ?0.1 | Flavoring agent |
| Water | To 100ml | Solvent |
At first antiseptic and Entecavir are added and boiled in right amount and be cooled in about 40 ℃ to 80 ℃ water, stir fast, to the whole dissolvings of solid, add sweetener, buffer agent and flavoring agent then, finally regulate pH value to about 4.5 with citric acid or sodium citrate, with suitable quantity of water solution dilution is arrived final solvent then, sealing and storage at room temperature in the vial of packing into.
The stability of table 2 instant liquid entecavir composition (0.05mg/ml) in glass bottle packaging.
Embodiment 2
Table 3 is pressed the disclosed prescription preparation of CN03813287
Instant liquid Entecavir (0.05mg/ml) composition components
| Composition | Consumption (g/100ml) | Effect |
| Entecavir | ??0.005 | Active component |
| Maltose alcohol | ??65 | Sweetener |
| Citric acid | ??0.96 | The pH buffer agent |
| Sodium citrate | ?0.037 | The pH buffer agent |
| Methyl parahydroxybenzoate | ?0.2 | Antiseptic |
| Propyl p-hydroxybenzoate | ?0.028 | Antiseptic |
| Orange flavor | ?0.1 | Flavoring agent |
| Composition | Consumption (g/100ml) | Effect |
| Water | To 100ml | Solvent |
At first antiseptic and Entecavir are added and boiled in right amount and be cooled in about 40 ℃ to 80 ℃ water, stir fast, to the whole dissolvings of solid, add sweetener, buffer agent and flavoring agent then, finally regulate pH value to about 5.0 with citric acid or sodium citrate, with suitable quantity of water solution dilution is arrived final volume then, sealing and storage at room temperature in the vial of packing into.Table 4 is pressed the stability of instant liquid entecavir composition (0.5mg/ml) in glass bottle packaging of the disclosed prescription preparation of CN03813287.
Table 4 is pressed the disclosed prescription preparation of CN03813287
Instant liquid Entecavir (0.05mg/ml) composition stable data
Execute example 3
Table 5 instant powder entecavir composite
| Composition | Consumption (g/100g) | Effect |
| Entecavir | ??0.05 | Active component |
| Composition | Consumption (g/100g) | Effect |
| Sucralose | ??5 | Sweetener |
| Citric acid | ??5 | The pH buffer agent |
| Sodium citrate | ??3 | The pH buffer agent |
| Methyl parahydroxybenzoate | ??0.75 | Antiseptic |
| Propyl p-hydroxybenzoate | ??0.15 | Antiseptic |
| Orange flavor | ??0.5 | Flavoring agent |
| Lactose | To 100g | Diluent |
The powder that the present invention prepares the Entecavir fluid composition can be made by following technology: the mode that Entecavir, sweetener, pH buffer agent, antiseptic, flavoring agent and diluent are progressively increased with equivalent stirs at mixer, amount by 1g powder/bag is packaged in the aluminium plastic bag then, during use mixture of powders added that stirring and dissolving gets final product in an amount of water, take one bag at every turn.
Table 6 instant powder entecavir composite stability
Claims (10)
1. low dosage ready-to-use entecavir composite, it is characterized in that: for containing the composition of liquid medicine of Entecavir, pH value is 3-7, comprises
A) concentration in suitable pharmacy acceptable solvent is the Entecavir of 0.001%-20%w/v;
B) concentration is the sweetener of 0.01%-10%w/v; With
C) concentration is the buffer agent of 0.01%-5%w/v.
2. low dosage ready-to-use entecavir composite according to claim 1 is characterized in that: the concentration of described Entecavir is 0.005%-5%w/v.
3. low dosage ready-to-use entecavir composite according to claim 1 is characterized in that: described sweetener is selected from one or more in sucralose, aspartame and the steviosin, and its concentration is 0.01%-2%w/v.
4. low dosage ready-to-use entecavir composite according to claim 1 is characterized in that: described buffer agent is selected from one or more in citrate buffer, phosphate buffer and the acetate buffer, and its concentration is 0.1%-3%w/v.
5. low dosage ready-to-use entecavir composite according to claim 1 is characterized in that: further comprise at least a following component that is selected from: antiseptic, flavoring agent and pH regulator agent; Antiseptic is selected from one or more in oxybenzene ester series, benzoic acid series and the sorbic acid series, and concentration is 0.01%-2%w/v; Flavoring agent is selected from orange flavor or grape essence, and its concentration is 0.01% to 2%w/v.
6. low dosage ready-to-use entecavir composite, it is characterized in that: for containing the powder composition of Entecavir, pH value is 3-7, and it comprises
A) account for the Entecavir of powder composition gross weight 0.001wt.%-20wt.%;
B) account for the sweetener of powder composition gross weight 0.01wt.%-10wt.%; With
C) account for the buffer agent of powder composition gross weight 1wt.%-20wt.%.
7. low dosage ready-to-use entecavir composite according to claim 6 is characterized in that: the 0.005wt.%-5wt.% of described entecavir powder composition gross weight.
8. low dosage ready-to-use entecavir composite according to claim 6 is characterized in that: described sweetener is selected from one or more in sucralose, aspartame and the steviosin.
9. low dosage ready-to-use entecavir composite according to claim 6 is characterized in that: described buffer agent is selected from one or more in citrate buffer, phosphate buffer and the acetate buffer.
10. low dosage ready-to-use entecavir composite according to claim 6 is characterized in that: also comprise at least a following component that is selected from: antiseptic, flavoring agent and its combination in any; Antiseptic is selected from one or more in oxybenzene ester series, benzoic acid series and the sorbic acid series, and its content is that about 0.01wt.% is to 5wt.%; Flavoring agent is selected from orange flavor or grape essence, and content is that 0.001wt.% is to 2wt.%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910082230A CN101869569A (en) | 2009-04-21 | 2009-04-21 | Ready-to-use entecavir composite |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910082230A CN101869569A (en) | 2009-04-21 | 2009-04-21 | Ready-to-use entecavir composite |
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| Publication Number | Publication Date |
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| CN101869569A true CN101869569A (en) | 2010-10-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910082230A Pending CN101869569A (en) | 2009-04-21 | 2009-04-21 | Ready-to-use entecavir composite |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103301071A (en) * | 2013-06-03 | 2013-09-18 | 北京阜康仁生物制药科技有限公司 | Stable entecavir sugarless granules and preparation method thereof |
| CN109984996A (en) * | 2018-01-02 | 2019-07-09 | 扬子江药业集团有限公司 | Entecavir oral administration solution and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1658844A (en) * | 2002-04-08 | 2005-08-24 | 布里斯托尔-迈尔斯斯奎布公司 | Low dose liquid entecavir formulations and use |
| CN101204395A (en) * | 2006-12-19 | 2008-06-25 | 北京德众万全药物技术开发有限公司 | Orally disintegrating entecavir tablets |
-
2009
- 2009-04-21 CN CN200910082230A patent/CN101869569A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1658844A (en) * | 2002-04-08 | 2005-08-24 | 布里斯托尔-迈尔斯斯奎布公司 | Low dose liquid entecavir formulations and use |
| CN101204395A (en) * | 2006-12-19 | 2008-06-25 | 北京德众万全药物技术开发有限公司 | Orally disintegrating entecavir tablets |
Non-Patent Citations (2)
| Title |
|---|
| 郑建仙: "《功能性食品甜味剂》", November 1997 * |
| 阚建全: "《食品化学》", September 2002 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103301071A (en) * | 2013-06-03 | 2013-09-18 | 北京阜康仁生物制药科技有限公司 | Stable entecavir sugarless granules and preparation method thereof |
| CN109984996A (en) * | 2018-01-02 | 2019-07-09 | 扬子江药业集团有限公司 | Entecavir oral administration solution and preparation method thereof |
| CN109984996B (en) * | 2018-01-02 | 2022-01-18 | 扬子江药业集团有限公司 | Entecavir oral solution and preparation method thereof |
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Application publication date: 20101027 |