CN100374118C - Drip pill agent containing adefovir divoxil and its preparing method - Google Patents
Drip pill agent containing adefovir divoxil and its preparing method Download PDFInfo
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- CN100374118C CN100374118C CNB2004100448052A CN200410044805A CN100374118C CN 100374118 C CN100374118 C CN 100374118C CN B2004100448052 A CNB2004100448052 A CN B2004100448052A CN 200410044805 A CN200410044805 A CN 200410044805A CN 100374118 C CN100374118 C CN 100374118C
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Abstract
The present invention relates to an oral medicine preparation of adefovir dipivoxil drop pills and a preparation process thereof. Adefovir dipivoxil, substrates and film coatings are contained in a medicament. When preparation, firstly, the substrates and the medicine are heated to the molten state; then, the substrates and the medicines are condensed into pills in cooling liquid by a dropping method; cooling liquid is removed; the drop pills are prepared by drying, and the coatings are obtained. Compared with the existing preparation of the adefovir dipivoxil, the present invention has the advantages of high biologic availability and flexible administration dosage.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of adefovir ester drop pill for the treatment of hepatitis B virus, be used for the treatment of hepatitis B.
Background technology
Chronic hepatitis B is the major disease of serious threat human health and life, is commonly encountered diseases and frequently-occurring disease.According to statistics, China's hepatitis B virus carriers is sent out the patient more than 1,500 ten thousand more than 100,000,000 people.For a long time, chronic viral hepatitis B lacks effective medicine always, and the chronic viral hepatitis B medicine that minority is newer all has bigger shortcoming, and as acycloguanosine curative effect 30-40% only, the alpha-interferon side reaction is serious and cost an arm and a leg.Curative effect new drug lamivudine preferably easily produces drug resistance, and viremia appears in most patient after the drug withdrawal.Therefore, development curative effect height, the anti-chronic viral hepatitis B new drug that toxic and side effects is low is the task of top priority.
Adefovir ester is up-to-date anti-chronic viral hepatitis B medicine, is AG14361 and reverse transcriptase inhibitors, and the activity of very high anti-chronic viral hepatitis B virus (HBV) DNA is arranged, and can reduce the hepatitis B virus e antigen in blood and the seropositive conversion.In in vitro tests, lamivudine and the drug-fast a series of HBV of famciclovir there is pair resistant activity.Though this product also has toxicity, incidence rate is few, reaction is lighter.Compare with lamivudine, the most outstanding advantage of this product is be difficult for to produce drug resistance, does not find that drug resistance produces in the clinical research that the clinical research and the second stage of open label of all blanks of three phases 48 reached for 136 weeks.Therefore, adefovir ester is present best anti-chronic viral hepatitis B new drug.
Adefovir ester is developed by Gilead Science and Bristol-Myers Squibb Co. two companies, be broad-spectrum antiviral drug, many viruses all there is pair resistant activity, comprise HIV (HIV (human immunodeficiency virus)), HBV (hepatitis B virus), HCMV (human cytomegalic inclusion disease virus), HSV-I, II (I, II type herpesvirus), MSV (moloneys mouse sarcoma virus), FLV (blood friend leucovirus).But be mainly used in hepatitis B.Be considered to that better, the clinical consumption of curative effect is less, safety good and adopted unanimously by U.S. FDA antiviral committee.
What patent CN1251592A protected is crystal type adefovirdipivoxil ester composition, although it has the advantage of good stability, the molten diffusing time is long, makes absorption of human body slow.
Summary of the invention
The object of the present invention is to provide a kind of adefovir ester drop pill and preparation method thereof that contains, adefovir ester exists with the state of solid dispersion in this dose, and its stripping is fast, the bioavailability height, and steady quality, easy to use effective.
Technical scheme of the present invention is: a kind of drop pill that contains adefovir ester, it comprises adefovir ester, the drop pill core that substrate constituted, there is coating the outside of described drop pill core, described substrate be under the room temperature condition below 40 ℃ for medicinal substrate stationary state, that can form drop pill, be one or more the mixture in solid polyethylene glycol, polyoxyethylene (40) monostearate, poloxamer, carbamide, monostearate, octadecanol, hexadecanol, glyceryl monostearate, the tween.
A kind of preparation method that contains the drop pill of adefovir ester, it comprises the steps: that an adefovir ester, substrate are heated to molten condition, splashes into to be condensed into ball in the liquid coolant, removes liquid coolant, dry drop pill core; Described liquid coolant comprises one of dimethicone, liquid paraffin, vegetable oil or its mixture.
Good effect of the present invention is: in order to improve the water solublity of adefovir ester, we make the solid dispersion of its cooling formation drop pill shape again with the substrate molten condition mixing of adefovir ester and drop pill, improve the dissolubility and the bioavailability of medicine.When the part by weight of adefovir ester and substrate is 1: 16 when above, through the X-diffraction experiment, the crystal formation of adefovir ester disappears, and solid dispersion forms.
The invention provides a kind of adefovir ester dropping pill formulation and preparation technology thereof, wherein adefovir ester exists with the state of solid dispersion, it is molten diffusing fast to have disintegrate, dissolution rate and dissolution height, steady quality, the pill volume is little, easy to carry and use, dosage is flexible, is fit to old man, child and dysphagia person and takes the characteristics that compliance is good.Also has production equipment and working condition is simple, the characteristics that production cost is low.
Adefovir ester is tablet and capsule for existing dose, and prior art is compared with it with drop pill provided by the present invention, and bioavailability of the present invention is higher.We use rabbit as experimental animal, bioavailability to adefovir ester tablet, capsule and drop pill has been carried out contrast test, the result shows that this drop pill under the blood drug level-time graph of the oral back of rabbit is 9～12 times of tablet, is 7～10 times of capsule.As seen the bioavailability of adefovir ester drop pill is high than other preparations.
Cause the unsettled characteristics of preparation according to the adefovir ester facile hydrolysis, the drop pill that we select, make in the preparation process, get along well fully water contact of medicine, again the drop pill that forms solid dispersion has been carried out coating, substantially avoid contacting of medicine and water, made the good stability of adefovir ester in this kind preparation form.We have carried out stability test to the adefovir ester drop pill that obtains.
1,40 ℃ of accelerated tests
Get 3 batches of adefovir ester drop pill, put in 40 ℃ of calorstats and stored 6 months, detect by the study on the stability project,, investigate and the results are shown in Table 1 result and comparison in 0 month in 1st month, 2 months, 3 months, 6 samplings at the end of month.
40 ℃ of accelerated tests of table 1 adefovir ester drop pill are investigated the result
| Time (moon) | Lot number | The investigation project | ||
| Related substance (%) | Disintegration | Content (%) | ||
| 1 | 030616 030617 030618 | 2.11 2.22 1.85 | Up to specification up to specification | 99.5 100.0 101.2 |
| 2 | 030616 030617 030618 | 2.21 2.16 2.00 | Up to specification up to specification | 99.0 99.5 96.5 |
| 3 | 030616 030617 030618 | 2.25 2.28 2.64 | Up to specification up to specification | 102.5 98.6 97.1 |
| 6 | 030616 030617 030618 | 2.47 2.88 2.87 | Up to specification up to specification | 100.7 101.8 103.6 |
The result shows: the adefovir ester drop pill is after storing 6 months under 40 ℃ of conditions, and every index has no significant change, and adefovir ester drop pill constant product quality is described.
2, long term test
3 batches of the adefovir ester drop pill of trial-production were stored 9 months at ambient temperature, respectively at sampling in 3rd month, 6 months, 9 months, detect by the study on the stability project, and with 0 month relatively, investigate and the results are shown in Table 2.
Table 2 adefovir ester drop pill long term test is investigated the result
| Time (moon) | Lot number | The investigation project | ||
| Related substance (%) | Disintegration | Content (%) | ||
| 0 | 030616 030617 030618 | 0.78 0.91 0.99 | Up to specification up to specification | 103.4 103.2 102.1 |
| 3 | 030616 030617 030618 | 0.83 0.81 0.95 | Up to specification up to specification | 103.4 99.4 98.0 |
| 6 | 030616 030617 030618 | 1.16 1.17 1.29 | Up to specification up to specification | 103.6 102.8 102.9 |
| 9 | 030616 030617 030618 | 1.20 1.38 1.34 | Up to specification up to specification | 98.4 101.0 102.0 |
Above result shows: the adefovir ester drop pill is after storing 9 months under 25 ℃ of conditions, and every index has no significant change, and adefovir ester drop pill constant product quality is described.
The specific embodiment:
A kind of drop pill that contains adefovir ester, it comprises adefovir ester, the drop pill core that substrate constituted, there is coating the outside of described drop pill core, described substrate is for stationary state under the room temperature condition below 40 ℃, can form the medicinal substrate of drop pill, definition according to pharmaceutical book, substrate requires fusing point low, its fusing point is below 100, suitable hardness is arranged under the room temperature condition of 10-30 degree Celsius, softening not non-caked, have after oral needed solubility property is arranged, can not be dissolved in employed liquid coolant during preparation, can form solution when melting with medicine, steady quality under the fusing heating status has the better chemical inertia, do not work with medicine, do not hinder the therapeutical effect of medicine yet, harmless, can be condensed into drop pill.It for example is one or more the mixture in solid polyethylene glycol, polyoxyethylene (40) monostearate, poloxamer, carbamide, monostearate, octadecanol, hexadecanol, glyceryl monostearate, the tween.
Described coating is that sugar-coat or described coating are film-coat, film-coat is defined as: the aggretion type material, avirulence, easy to operate, suitable solubility curve is arranged, even when having the color of Powdered additive to exist, the ability that forms hard and tool elasticity clothing film is also arranged, the clothing film to heat, light, moisture and the medicine that wraps stable, and do not have uncomfortable abnormal smells from the patient, the clothing film is airtight, permeable, can dissolve or decompose under some specific pH condition of digestive tract, the clothing film has suitable intensity, does not change at long lay up period.
Described film-coat is one of cellulose ether, acrylate copolymer, methyl-propyl acid ester copolymer, ethyl cellulose, cellulose acetate phthalate ester, methacrylic acid copolymer, Lac, polyvinyl alcohol phthalate ester, benzenetricarboxylic acid acetyl cellulose, Opadry or its mixture.
The weight proportion of described adefovir ester and substrate is 1: 16～40.
Containing adefovir ester in described every drop pill core is the 0.1-10 milligram, in described every drop pill core
Containing adefovir ester is the 0.1-2.5 milligram.
A kind of preparation method that contains the drop pill of adefovir ester, it comprises the steps:
Adefovir ester, substrate are heated to molten condition, splash into and be condensed into ball in the liquid coolant, remove liquid coolant, dry drop pill core; Described liquid coolant comprises one of dimethicone, liquid paraffin, vegetable oil or its mixture.
During heating, get substrate earlier and be heated to molten condition, add adefovir ester in the substrate under molten condition again, stir, splash under the heat-retaining condition and be condensed into ball in the liquid coolant.
Embodiment 1:
Adefovir ester 10g
Polyethylene glycol 6000 160g
Hypromellose is an amount of
Embodiment 2:
Adefovir ester 10g
Monostearate 200g
The polyvinyl alcohol phthalate ester is an amount of
Embodiment 3:
Adefovir ester 10g
Polyethylene glycol 6000 200g
Macrogol 4000 50g
Hydroxyethyl-cellulose is an amount of
Embodiment 4:
Adefovir ester 10g
Glyceryl monostearate 60g
Macrogol 4000 150g
Methacrylic acid amino ester copolymer is an amount of
Above an amount of finger can wrap the drop pill core and get final product.
Claims (10)
1. drop pill that contains adefovir ester, it is characterized in that: it comprises adefovir ester, the drop pill core that substrate constituted, described substrate is to be medicinal substrate stationary state, that can form drop pill under 40 ℃ of following conditions, and the weight proportion of described adefovir ester and substrate is 1: 16～40.
2. the drop pill that contains adefovir ester according to claim 1 is characterized in that: there is coating the outside of described drop pill core.
3. the drop pill that contains adefovir ester according to claim 1 is characterized in that: described substrate is one or more the mixture in solid polyethylene glycol, polyoxyethylene (40) stearate, poloxamer, carbamide, monostearate, octadecanol, hexadecanol, glyceryl monostearate, the tween.
4. the drop pill that contains adefovir ester according to claim 1 is characterized in that: described coating is a sugar-coat.
5. the drop pill that contains adefovir ester according to claim 1 is characterized in that: described coating is a film-coat.
6. the drop pill that contains adefovir ester according to claim 5 is characterized in that: described film-coat is one of cellulose ether, acrylate copolymer, methyl-propyl acid ester copolymer, ethyl cellulose, cellulose acetate phthalate ester, methacrylic acid copolymer, Lac, polyvinyl alcohol phthalate ester, benzenetricarboxylic acid acetyl cellulose, Opadry or its mixture.
7. the drop pill that contains adefovir ester according to claim 1 is characterized in that: containing adefovir ester in described every drop pill core is the 0.1-10 milligram.
8. the drop pill that contains adefovir ester according to claim 7 is characterized in that: containing adefovir ester in described every drop pill core is the 0.1-2.5 milligram.
9. the preparation method that contains the drop pill of adefovir ester as claimed in claim 1, it is characterized in that: it comprises the steps:
Adefovir ester, substrate are heated to molten condition, splash into and be condensed into ball in the liquid coolant, remove liquid coolant, dry drop pill core;
Described liquid coolant is one of dimethicone, liquid paraffin, vegetable oil or its mixture.
10. the preparation method that contains the drop pill of adefovir ester according to claim 9, it is characterized in that: get substrate earlier and be heated to molten condition, add adefovir ester in the substrate under molten condition again, stir, splash under the heat-retaining condition and be condensed into ball in the liquid coolant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100448052A CN100374118C (en) | 2004-05-20 | 2004-05-20 | Drip pill agent containing adefovir divoxil and its preparing method |
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| CNB2004100448052A CN100374118C (en) | 2004-05-20 | 2004-05-20 | Drip pill agent containing adefovir divoxil and its preparing method |
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| CN1579406A CN1579406A (en) | 2005-02-16 |
| CN100374118C true CN100374118C (en) | 2008-03-12 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1799550B (en) * | 2005-01-04 | 2010-12-29 | 沈阳药科大学 | Highly efficient formulation of hepsera and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1251592A (en) * | 1997-07-25 | 2000-04-26 | 吉尔利德科学股份有限公司 | Nucleotide analog composation |
| CN1374314A (en) * | 2002-03-13 | 2002-10-16 | 上海仲夏化学有限公司 | Amorphous Adefuweizhi ester amorphous solid matter and its prepn |
| CN1429555A (en) * | 2002-12-27 | 2003-07-16 | 陈新民 | Adfuwei ester soft capsule and its preparation method |
-
2004
- 2004-05-20 CN CNB2004100448052A patent/CN100374118C/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1251592A (en) * | 1997-07-25 | 2000-04-26 | 吉尔利德科学股份有限公司 | Nucleotide analog composation |
| CN1374314A (en) * | 2002-03-13 | 2002-10-16 | 上海仲夏化学有限公司 | Amorphous Adefuweizhi ester amorphous solid matter and its prepn |
| CN1429555A (en) * | 2002-12-27 | 2003-07-16 | 陈新民 | Adfuwei ester soft capsule and its preparation method |
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| Publication number | Publication date |
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| CN1579406A (en) | 2005-02-16 |
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Owner name: JIANGSU WUZHONG MEDICINE GROUP CO., LTD. Free format text: FORMER OWNER: JIANGSU WUZHONG CHINESE MEDICINE RESEARCH AND DEVELOPMENT CO., LTD. Effective date: 20091113 |
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Effective date of registration: 20091113 Address after: 8, No. 2 Wu Dong South Road, Jiangsu, Suzhou Patentee after: Jiangsu Wuzhong Medical Group Co.,Ltd. Address before: No. 2, Soochow South Road, Jiangsu, Suzhou Patentee before: Wuzhong Chinese Medicines Research & Development Co., Ltd., Jiangsu |
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Effective date of registration: 20160918 Address after: 215168, No. 2, Soochow South Road, Suzhou, Jiangsu, 8 Patentee after: Jiangsu Wuzhong Medical Group Co.,Ltd. Patentee after: Jiangsu Wuzhong Pharmaceutical Group Co., Ltd. Suzhou pharmaceutical factory Address before: 215168, No. 2, Soochow South Road, Suzhou, Jiangsu, 8 Patentee before: Jiangsu Wuzhong Medical Group Co.,Ltd. |