U.S. patent application number 10/581370 was filed with the patent office on 2008-01-24 for butylphtualide soft gel capsule and its preperation procedure.
Invention is credited to Min Bai, Surui Chen, Wenmin Guo, Jianqing Li, Liyun Liu, Guirong Zhou.
Application Number | 20080020034 10/581370 |
Document ID | / |
Family ID | 34638049 |
Filed Date | 2008-01-24 |
United States Patent
Application |
20080020034 |
Kind Code |
A1 |
Li; Jianqing ; et
al. |
January 24, 2008 |
Butylphtualide Soft Gel Capsule and Its Preperation Procedure
Abstract
The present invention discloses a novel dosage form of
butylphthalide soft capsule and its preparation procedure.
Butylphthalide soft capsule is composed of a coating material and a
drug-containing oil. The drug-containing oil is basically composed
of butylphthalide and diluent--vegetable oil, wherein the weight
ratio of butylphthalide to oil ranges from 1:0-10. The coating
material is composed of gelatin, plasticizer and water, wherein the
weight ratio of gelatin to plasticizer to water is in the range of
1:0.2{tilde over ( )}0.4:0.8{tilde over ( )}0.3. The butylphthalide
soft capsule described in this invention can mask the strong and
specific flavor of butylphthalide, and overcome the difficulties
associated with formulating oily active agents into other oral
preparations. The disintegration time of the soft capsule complies
with the requirement of Pharmacopoeia of P.R. China.
Inventors: |
Li; Jianqing; (Shijiazhung,
CN) ; Bai; Min; (Shijiazhuang, CN) ; Guo;
Wenmin; (Shijiazhuang, CN) ; Chen; Surui;
(Shijiazhuang, CN) ; Liu; Liyun; (Shijiazhuang,
CN) ; Zhou; Guirong; (Shijiazhuang, CN) |
Correspondence
Address: |
Knobbe Martens Olson & Bear LLP
550 West C Street, Suite 1200
San Diego
CA
92101
US
|
Family ID: |
34638049 |
Appl. No.: |
10/581370 |
Filed: |
December 3, 2004 |
PCT Filed: |
December 3, 2004 |
PCT NO: |
PCT/CN04/01411 |
371 Date: |
September 12, 2007 |
Current U.S.
Class: |
424/456 ;
424/451; 514/470 |
Current CPC
Class: |
A61K 9/4825 20130101;
A61K 9/4816 20130101; A61P 7/02 20180101; A61P 9/10 20180101; A61K
31/365 20130101; A61K 9/4875 20130101; A61K 31/34 20130101 |
Class at
Publication: |
424/456 ;
424/451; 514/470 |
International
Class: |
A61K 9/48 20060101
A61K009/48; A61K 31/34 20060101 A61K031/34 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 5, 2003 |
CN |
200310119336.1 |
Claims
1. A butylphthalide soft gel capsule characterized by a composition
comprising capsule materials and pharmaceutical components in
drug-containing oil form, wherein the pharmaceutical components in
drug-containing oil comprising substantially butylphthalide and
vegetable oil with the weight ratio in between 1:0 and 1:10.
2. The butylphthalide soft gel capsule according to claim 1,
wherein the characterized weight ratio between butylphthalide and
vegetable oil ranges from 1:1 to 1:8.
3. The butylphthalide soft gel capsule according to claim 2,
wherein the characterized weight ratio of said butylphthalide and
said vegetable oil ranges from 1:2 to 1:5.
4. The butylphthalide soft gel capsule according to claim 3,
wherein the characterized weight ratio between butylphthalide and
vegetable oil is 1:3.5.
5. The butylphthalide soft gel capsule according to claim 1,
wherein the characterized vegetable oil is selected from the group
consisting of sesame oil, corn oil, peanut oil, soybean oil, almond
oil, peach kernel oil, cottonseed oil, sunflower seed oil, olive
oil, or their mixture.
6. The butylphthalide soft gel capsule according to claim 1,
wherein the characterized butylphthalide includes the optically
inactive, mixed L and D forms of butylphthalide, levorotatory
optical isomer of butylphthalide, dextrorotatory optical isomer of
butylphthalide.
7. The butylphthalide soft gel capsule according to claim 1,
wherein the characterized drug-containing oil further includes
dibutyl carboxyl methyl benzene (dibutyl carboxyl toluene) as
antioxidant with 0 to 0.2% weight ratio in respect to
drug-containing oil.
8. The butylphthalide soft gel capsule according to claim 1,
wherein the characterized capsule materials includes the basic
components of gel, plasticizer and water with the weight ratio of
1:0.2 to 0.4:0.8 to 1.3.
9. The butylphthalide soft gel capsule according to claim 8,
wherein the characterized gel is selected from the group consisting
of gelatin or acacia gum (Gum Arabic), or a mixture of gelatin and
acacia gum.
10. The butylphthalide soft gel capsule according to claim 8,
wherein the characterized plasticizer is selected from the group
consisting of glycerol (glycerin) or sorbitol (sorbierite), or a
mixture of glycerol and sorbitol.
11. The butylphthalide soft gel capsule according to claim 8,
wherein the characterized capsule materials further includes
antiseptic agents.
Description
TECHNICAL FIELD
[0001] This invention relates to a novel dosage form of
butylphthalide soft gel capsules and its preparation.
BACKGROUND ART
[0002] Butylphthalide is a major ingredient of celery (Apium
graveolens) and its seeds. It can be extracted from seed oil of
natural celery, or obtained from chemical synthesis. Chinese patent
98125618. X disclosed applications of L-butylphthalide
(levorotatory butylphthalide) in drugs of anti thrombosis and anti
platelet aggregation, which clearly demonstrated that
butylphthalide has a function of adjusting NOS-NO-cGMP system and
nerve cell arachidonic acid metabolism after brain ischemia.
Chinese patent 93117148.2 disclosed applications of Apigenin A in
preparing of medicine for prevention and treatment of the diseases
caused by brain ischemia in mammals and human. Apigenin A is in
fact the non-optically active form of butylphthalide.
Butylphthalide is an oily liquid with strong celery smell. The
chemical structure of butylphthalide is as following:
##STR00001##
[0003] The soft gel capsule is a relatively new form of
pharmaceutical delivery system, which is especially suitable for
orally delivering active ingredients in oil form. The main active
ingredient is uniformly distributed in the diluting agents and the
drug dosage is measured accurately in each capsule. The out surface
of the capsule is smooth and round, so that the capsule can be
easily swallowed by the patient, therefore the patient compliance
of the soft gel capsule is good.
DISCLOSURE OF THE INVENTION
[0004] This invention discloses a novel butylphthalide soft gel
capsule form based on our research and development on the physical
and chemical characteristic of butylphthalide and utilization of
the special advantage of soft gel capsule.
[0005] The purpose of the invention is to provide a butylphthalide
soft gel capsule.
[0006] This invention, butylphthalide soft gel capsule, is
comprised of capsule materials and drug-containing oil, in which
the drug-containing oil is comprised of butylphthalide and diluent
vegetable oil basically. The weight ratio between butylphthalide
and diluent vegetable oil ranges from 1:0 to 1:10 (w/w). Besides
the main ingredients of the drug-containing oil, certain amount of
antioxidant dibutyl carboxyl methyl benzene (dibutyl carboxyl
toluene) can be added to the vegetable oil.
[0007] Butylphthalide in this invention means the optically
inactive, mixed L and D forms of butylphthalide, and/or
levorotatory optical isomer of butylphthalide, and/or
dextrorotatory optical isomer of butylphthalide. Their appearances
are all in the oily liquid form.
[0008] The vegetable oil can be selected from a group of oils
consisting of sesame oil, corn oil, peanut oil, soybean oil, almond
oil, peach kernel oil, cottonseed oil, sunflower seed oil, olive
oil, or a mixture of them.
[0009] Capsule materials are basically comprised of gel materials,
plasticizer and water. The composition weight ratio between gel,
plasticizer and water is: 1:0.2 to 0.4:0.8 to 1.3. Suitable
antiseptic agents can be added to the capsule materials, such as
ethyl p-hydroxybenzoate or methyl p-hydroxybenzoate.
[0010] Gel materials can be selected from one of gelatin or acacia
gum (Gum Arabic), or a mixture of the two.
[0011] Plasticizer, which makes the capsule soft and elastic, can
be selected from one of glycerol (glycerin) or sorbitol
(sorbierite), or a mixture of the two.
[0012] In this invention butylphthalide soft gel capsule can be
made by a number of conventional soft gel capsule manufacture
methodologies, such as manually molding press method, rotary
molding press method or dripping molding method. Usually we select
press method such as rotary molding press method. We use automatic
rotary capsule molding presser, control its working temperature at
40 to 50 degree C., and ensure each molded soft gel capsule
containing sufficient butylphthalide for medicinal use.
[0013] This invention chooses the soft gel capsule as a new
pharmaceutical delivery form for butylphthalide, which is able to
mask its characteristic strong smell. Meanwhile the new
preparation, soft gel capsule, overcomes the difficulty of other
oral delivery forms of delivering oily active ingredients to
patients. The patients can conveniently take the oval shaped soft
gel capsule orally and easily swallow them. The patients'
compliance of the new delivery form preparation is good.
MODES OF CARRYING OUT THE INVENTION
[0014] In this invention, butylphthalide soft gel capsule is
comprised of capsule materials and drug-containing oil, in which
the drug-containing oil is comprised basically of butylphthalide
and diluent vegetable oil. A relatively better weight ratio of
butylphthalide to diluent vegetable oil ranges from 1:1 to 1:8
(w/w). The further better selected weight ratio of butylphthalide
to diluent vegetable oil ranges from 1:2 to 1:5 (w/w). In the best
mode, the weight ratio of butylphthalide to diluent vegetable oil
is 1:3.5 (w/w). Dibutyl carboxyl methylbenzene (dibutyl carboxyl
toluene) as an antioxidant with the amount of 0 to 0.2% (weight
ratio) can be further added to drug-containing oil.
[0015] A better choice of vegetable oil can be selected from a
group of oils consisting of peanut oil, soybean oil, corn oil, and
sesame oil. The best mode choice of oil is soybean oil.
[0016] Capsule materials are basically comprised of gel,
plasticizer and water. Among them, the best mode choice of gel is
gelatin, the best mode choice of plasticizer is glycerol.
[0017] The following implemented experiments are given to further
describe the technical scheme of this invention better. The
foregoing description is intended to illustrate and not limit the
scope of the invention.
Experiment 1
Preparation of Butylphthalide Soft Gel Capsules
[0018] Preparation of Gelatin Liquid:
[0019] Gelatin 100 grams, glycerol 30 grams, water 130 grams and
200 mg ethyl p-hydroxybenzoate.
[0020] Took gelatin and add certain amount of water, let gelatin
absorb water and expend. Meanwhile, put glycerol, ethyl
p-hydroxybenzoate, and the rest of the water into a colloidal sol
pot, heated them to the temperature of 70 to 80 degree C., mixed
them well, then added the water absorbed and expended gelatin into
the pot and stirred them thoroughly till they were melted. Kept the
temperature of the pot stable for 1 to 2 hours, kept the gel liquid
in the pot stable and let it settle down so that the air bubbles in
the gel liquid floated to the surface of it. Scraped the bubbles
off the gel liquid surface. Used a piece of clean white cloth
filtering the gel liquid. Kept the gel liquid temperature stable
and waited for its further use. The viscosity of the gelatin liquid
is usually 2.8 to 3.2 degree.
[0021] Preparation of Drug-Containing Oil:
[0022] Weighed butylphthalide 100 grams, stirred it thoroughly and
mixed it well with clear soybean oil 350 grams. The drug-containing
oil was ready for use.
[0023] Press Preparation of Soft Gel Capsules:
[0024] Took prepared gelatin glycerol liquid and butylphthalide
drug-containing oil and put each of them into automatic rotary
molding capsule presser, controlled its working temperature at 40
to 50 degree C., pressed and produced butylphthalide soft gel
capsules, each of them contains 450 mg of drug-containing oil.
[0025] The soft gel capsules press produced according to Experiment
1 method and contained Experiment 1 ratio of drug-containing oil,
were in proper outside measurement sizes. The quality test result
revealed that they contained uniformly distributed amount of
drug-containing oil in each of the capsule. The detailed results
were as follows:
TABLE-US-00001 Sample Capsule 1 Capsule 2 Capsule 3 Capsule 4
Capsule 5 Capsule 6 Capsule 7 Capsule 8 Capsule 9 Capsule 10
Content 99.12 98.08 100.02 99.47 99.32 101.38 98.65 98.76 99.25
98.47 (%) Range of 98.08-101.38 Content (%) Standard 0.93 Deviation
(%)
Experiment 2
Preparation of Butylphthalide Soft Gel Capsules
[0026] All the rest preparing steps were the same as the steps in
Example 1, except that during the preparation of drug-containing
liquid steps we did not add any vegetable oil, therefore the final
press produced soft gel capsules contained 100 mg drug-containing
liquid in each of the capsule.
Experiment 3
Preparation of Butylphthalide Soft Gel Capsules
[0027] Preparation of Gelatin Liquid:
[0028] gelatin 100 grams, glycerol 40 grams, water 120 grams and
200 mg ethyl p-hydroxybenzoate. The rest preparation steps were the
same as in Experiment 1.
[0029] Preparation of Drug-Containing Oil:
[0030] Weighed butylphthalide 225 grams, stirred it thoroughly and
mixed it well with clear peanut oil 225 grams. The drug-containing
oil was ready for use.
[0031] Press Preparation of Soft Gel Capsules:
[0032] All the rest preparing steps were the same as the steps in
above mentioned other Experiments, except that the final press
produced soft gel capsules contained 200 mg drug-containing oil in
each of the capsule.
[0033] The soft gel capsules press produced according to Experiment
3 method and contained Experiment 3 ratio of drug-containing oil,
were tested. The test results were as follows:
TABLE-US-00002 Sample Capsule 1 Capsule 2 Capsule 3 Capsule 4
Capsule 5 Capsule 6 Capsule 7 Capsule 8 Capsule 9 Capsule 10
Content 98.33 96.08 99.42 101.73 94.37 100.31 92.65 98.79 102.01
95.78 (%) Range of 92.65-102.01 Content (%) Standard 3.14 Deviation
(%)
Experiment 4
Preparation of Butylphthalide Soft Gel Capsules
[0034] All the rest preparing steps were the same as the steps in
Experiment 1, except during the preparation of drug-containing oil
steps we weighed butylphthalide 56.25 grams, stirred it thoroughly
and mixed it well with clear peanut oil 393.75 grams, therefore the
final press produced soft gel capsules contained 800 mg
drug-containing oil in each of the capsule.
[0035] The soft gel capsules pressed according to Experiment 4
method and contained Experiment 4 ratio of drug-containing oil,
were tested.
[0036] The test results are as follows:
TABLE-US-00003 Sample Capsule 1 Capsule 2 Capsule 3 Capsule 4
Capsule 5 Capsule 6 Capsule 7 Capsule 8 Capsule 9 Capsule 10
Content 100.03 99.08 99.42 101.73 98.57 100.31 99.55 98.99 100.11
99.98 (%) Range of 98.57-101.73 Content (%) Standard 0.88 Deviation
(%)
Experiment 5
Preparation of Butylphthalide Soft Gel Capsules
[0037] Preparation of Gelatin Liquid:
[0038] Gelatin 100 grams, glycerol 20 grams, water 80 grams and 200
mg ethyl p-hydroxybenzoate. The rest preparation steps were the
same as in Experiment 1.
[0039] Preparation of Drug-Containing Oil:
[0040] Weighed butylphthalide 45 grams, stirred it thoroughly and
mixed it well with clear peanut oil 405 grams. The drug-containing
oil is ready for use.
[0041] Press Preparation of Soft Gel Capsules:
[0042] All the rest preparing steps were the same as the steps in
above mentioned Experiments, except that the final press produced
soft gel capsules contained 1000 mg drug-containing oil in each of
the capsule.
Experiment 6
Preparation of Butylphthalide Soft Gel Capsules
[0043] All the rest preparing steps were the same as the steps in
Experiment 1, except that during the preparation of drug-containing
oil steps we weighed butylphthalide 90 grams, stirred it thoroughly
and mixed it well with clear soybean oil 360 grams, therefore the
final press produced soft gel capsules contained 500 mg
drug-containing oil in each of the capsule.
Experiment 7
Preparation of Butylphthalide Soft Gel Capsules
[0044] All the rest preparing steps were the same as the steps in
Experiment 1, except that during the preparation of drug-containing
oil steps we weighed butylphthalide 40.91 grams, stirred it
thoroughly and mixed it well with clear soybean oil 490.09 grams,
therefore the final press produced soft gel capsules contain 1100
mg drug-containing oil in each of the capsule.
Experiment 8
Preparation of Butylphthalide Soft Gel Capsules
[0045] All the rest preparing steps were the same as the steps in
Experiment 1, except that during the preparation of drug-containing
oil steps we weighed butylphthalide 50 grams, stirred it thoroughly
and mixed it well with clear soybean oil 400 grams, therefore the
final press produced soft gel capsules contained 900 mg
drug-containing oil in each of the capsule.
Experiment 9
Preparation of Butylphthalide Soft Gel Capsules
[0046] All the rest preparing steps were the same as the steps in
Experiment 1, except that during the preparation of drug-containing
oil steps we weighed butylphthalide 150 grams, stirred it
thoroughly and mixed it well with clear soybean oil 300 grams and
antioxidant ethyl p-hydroxybenzoate 0.45 grams, therefore the final
press produced soft gel capsules contained 300.3 mg drug-containing
oil in each of the capsule.
Experiment 10
Butylphthalide Content, Relevant Materials and Disintegrating Time
Limit Assay
[0047] Assay Method
[0048] Disintegrating Time Limit Assay
[0049] Disintegrating time limit assay was performed according to
Chinese Pharmacopoeia, Edition 2000, Part Two, Appendix VA's
Disintegrating Time Limit Assay.
[0050] Took samples from Experiment 1, used diluted hydrochloric
acid (9.fwdarw.1000) 1,000 ml as solvent, set testing temperature
at 37 degree C.+/-1 degree C., set speed of raising and submerging
the capsule at 30 to 32 times per minute, added baffle while
testing, and observed the total disintegrating time of each soft
gel capsule. The result indicated that the disintegrating time was
less than 1 hour, which pass the standard of Chinese
Pharmacopoeia.
[0051] Relevant Materials
[0052] Relevant materials were tested according to Chinese
Pharmacopoeia, Edition 2000, Part Two, Appendix VD's HPLC (High
Performance Liquid Chromatography) Assay.
[0053] Assay Method
[0054] Took adequate amount of content from this product, added
proper amount chloroform until it was dissolved. Added methanol up
to constant volume, diluted and prepared it with methanol until its
concentration was 0.5 mg per 1 ml. This was the test solution.
[0055] Weighed butylphthalide adequate amount as assay control
accurately, added methanol until it was dissolved, diluted and
prepared it with methanol to the concentration of 15 micro gram
(.mu.g) butylphthalide per 1 ml. This was the assay control
solution.
[0056] Measured assay control solution 20 micro liter (.mu.l)
accurately, ejected it into HPLC, tested it according to HPLC menu,
adjusted the sensitivity of HPLC until the major composition peak
measurement was 10 to 20% of the total measurement.
[0057] Measured test solution 20 micro liter (.mu.l) accurately,
tested it the same way as testing the assay control solution on
HPLC. Recorded chromatogram up to two folds of the retention time
of the chromatographic measurement of the major composition peak.
If impurity peaks were existed on the chromatogram, calculated the
areas of every impurity peak (except the solvent peak), and the
total areas of the impurity peaks should be no larger than the area
of the assay control solution peak.
[0058] Content Assay
[0059] Content was tested according to Chinese Pharmacopoeia,
Edition 2000, Part Two, Appendix VD's HPLC (High Performance Liquid
Chromatography) Assay.
[0060] Testing of Chromatographic Condition and System
Serviceability
[0061] Employed octadecyl silane bonded silica gel as filling,
methanol-water (65:35) as flow phase, set flow rate at 1.0 ml per
minute, assay wave length at 280 nm, theoretical board calculated
the number of butylphthalide peaks should be no less than 1500.
Butylphthalide versus impurity separation levels should be within
the standard.
[0062] Control Solution Preparation
[0063] Took butylphthalide control sample about 50 mg, weighed it
accurately, put it into a 50 ml graduated flask, added methanol
solution to dissolve it and diluted it up to the graduated mark,
mixed the solution thoroughly. Accurately measured 5 ml solution
from the flask and transferred it to another 50 ml graduated flask,
diluted it with methanol up to the graduated mark. This was control
solution.
[0064] Assay Solution Preparation
[0065] Took adequate amount of butylphthalide content from the
packages under the stock packaging difference (equivalent to about
butylphthalide 50 mg), weighed it accurately, put it into a 50 ml
graduated flask, added proper amount chloroform to dissolve it and
proper amount of methanol to dilute it up to the graduated mark,
stirred and mixed the solution thoroughly. Accurately measured 5 ml
solution from the flask and transferred it to another 50 ml
graduated flask, diluted it with methanol up to the graduated mark.
This was test solution.
[0066] Assay Method
[0067] Measured control solution 20 micro liter (.mu.l) and test
solution 20 micro liter (.mu.l) accurately, ejected both of them
into HPLC respectively, tested them according to HPLC menu, and
recorded their chromatograms respectively. Calculated the peak
areas of butylphthalide (C.sub.12H.sub.14O.sub.2) content according
to external standard method, recorded the data.
[0068] The experiment data as follows:
TABLE-US-00004 Observation Relevant Condition Content Substance
Disintegration Environment Time Appearance (%) (%) Time Initial 0
Day Yellow transparent soft gel capsule 98.8 0.61 4'50''
Accelerated 1 month Yellow transparent soft gel capsule 98.7 0.66
6'45'' Experiment 2 month Yellow transparent soft gel capsule 99.3
0.63 14'10'' 3 month Yellow transparent soft gel capsule 98.4 0.62
28'30'' 6 month Yellow transparent soft gel capsule 99.0 0.58
49'52'' Room 1 month Yellow transparent soft gel capsule 98.6 0.63
5'15'' Temperature 3 month Yellow transparent soft gel capsule 98.8
0.67 8'35'' Control 6 month Yellow transparent soft gel capsule
99.4 0.66 9'45'' Sample 12 month Yellow transparent soft gel
capsule 99.1 0.62 17'50'' 18 month Yellow transparent soft gel
capsule 98.5 0.64 27'25'' 24 month Yellow transparent soft gel
capsule 98.5 0.65 29'35''
[0069] Most soft gel capsule dosage forms suffer from the problem
of product disqualification due to disintegrating time limit when
the capsules pass extended shelf storage time. Even though, the
test results of accelerated assay and long term assay of the
present product indicate that the soft gel capsule shell ages fast
and disintegrating time changes more obviously under the heated
condition, the disintegrating time is less than 60 minutes. These
test results meet the standard of Chinese Pharmacopoeia, Edition
2000. All the indexes of appearance, content, relevant materials of
the soft gel capsule have passed the standard levels, and the
product's quality is guaranteed up to 2 years.
* * * * *