CN100435847C - Continuing release recipe of containing infusible basic remedy - Google Patents
Continuing release recipe of containing infusible basic remedy Download PDFInfo
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- CN100435847C CN100435847C CNB200410043476XA CN200410043476A CN100435847C CN 100435847 C CN100435847 C CN 100435847C CN B200410043476X A CNB200410043476X A CN B200410043476XA CN 200410043476 A CN200410043476 A CN 200410043476A CN 100435847 C CN100435847 C CN 100435847C
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Abstract
The present invention provides a durably releasing type oral combination in pharmacy, which is suitable for being taken every day. The oral combination contains at least one sovereign medicament (for example, erythromycin derivatives) difficult to dissolve. The oral combination in pharmacy contains the sovereign medicament, one kind of water soluble alginate, and one kind of organic carboxylic acid. The oral combination especially provides a controlling and releasing type lozenge of clarithromycin.
Description
Technical field
The present invention system is about difficult dissolubility principal agent, the oral lasting release formulation of erythromycin derivatives for example, and it can be digested in gastro-intestinal Fluid.The special system of the present invention about can every day one the ingot mode throw clarithromycin (clarithromycin) pharmaceutical compositions of clothes.
Background technology
The derivant of erythromycin and it all belongs to antibacterial, and they have antimicrbial power widely, with the antibacterial activity of penicillin have partly identical, particularly for gram-positive cocci, as enterococcus, Hemolytic streptococcus A group, streptococcus pneumoniae and staphylococcus, for effectively.Usually the dosage of taking is to take 2-4 time every day, takes continuously 10～14 days.For non-inpatient, take 2～4 every day and may cause inconvenience, maybe can forget and take; Therefore, preferably reduce the number of times of taking every day.Particularly to non-inpatient, solid-state lasting release formulation can reduce the number of times of taking.Lasting release formulation is to take 2～4 patients that take second place every day and avoid having when taking next ingot the situation of overdose to produce in order to make medicine maintain stable status at blood level with respect to the variation of time, so can to make.
It is known using alginate gel to prepare sustained release type lozenge.A kind of water miscible alginate, for example sodium alginate can react with calcium salt, so can make alginate be transformed into water-fast alginic acid Sodium glue.Type that can be by changing alginate molecular weight, alginate content, polyvalent cation and cross-linking agent and (or) cation measures containing in alginate, changes the sustained release character of alginate gel.United States Patent (USP) the 4th, 842 promptly has in No. 866 to disclose and utilizes sodium alginate and alginic acid Sodium to prepare solid-state sustained release dosage form.
Above-mentioned mentioned patented technology can not be applied in the prescription that contains the very low principal agent of water solublity, and for example, with the prescription that clarithromycin and alginate make, it is molten to there is no repeatability from too slow and its life body utilizability in the living animal test.For the very low medicine of water solublity, can utilize alginate for substrate and be added into organic acid, make solid-state sustained release dosage form.United States Patent (USP) the 5th, 705, No. 190 (it is equivalent to the TaiWan, China patent the 429th, No. 154) discloses a kind of sustained release dosage form, contains water-soluble alginate class, alginate complex and organic carboxyl acid (its can promote active component molten from).One of active component example is a clarithromycin, and it dissolves readily in the gastric juice, and in the easily dissolving of the position, upper end (pH 5.0) of small intestinal, is absorbed at this position clarithromycin most probable; But clarithromycin is difficult for dissolving at small intestinal lower end part (pH 6 to 8), so in order to be increased in the dissolubility at this position, use citric acid in prescription.United States Patent (USP) the 5th, 705, in the oral pharmaceutical composition that No. 190 are applied for, sodium alginate is about 16: 1 to 1: 1 to the weight ratio of alginic acid Sodium, and organic acid (for example citric acid) is 1: 1 to the mol ratio of principal agent.
At United States Patent (USP) the 5th, 705, in No. 190, the pharmaceutical compositions of its solid-state sustained release comprises sodium alginate, alginic acid Sodium and organic carboxyl acid (for example citric acid).Yet this prescription can't solve or reduce the side effect about the uncomfortable aspect of intestines and stomach, comprises symptoms such as nauseating, the vomiting and the sense of taste are not normal.In order to overcome above-mentioned these problems, therefore develop the improvement sustained release dosage form that to contain slightly solubility principal agent (for example erythromycin), as be described in United States Patent (USP) the 6th, 010, No. 718 persons.These prescriptions have comprised pharmaceutically acceptable high molecular polymer, as hydroxypropyl emthylcellulose, improve the sense of taste of rapid release dosage form, and reduce the side effect of intestines and stomach.United States Patent (USP) the 6th, 551,661B1 number and United States Patent (USP) the 6th, 010, No. 718 content is similar, but the former has comprised the side effect result of study of more intestines and stomach for patient, and the patient who continues release formulation that proof is taken clarithromycin significantly more can the drug withdrawal because of the intestines and stomach side effect, and the intestines and stomach side effect that these patients are taken place on one's body is significantly more not serious.
As United States Patent (USP) the 5th, 705, disclosed in No. 190,
XL ingot (Abbott Laboratories Ltd., Queenborough, Kent, ME11 5EL, Britain, clarithromycin continue to discharge ingot) contain 500 milligrams clarithromycin and other nonactive component as citric acid, sodium alginate, alginic acid Sodium, lactose, polyvidon (povidone), Pulvis Talci, stearic acid, magnesium stearate, hydroxypropyl emthylcellulose, propylene glycol, titanium dioxide (E1711), sorbic acid, quinoline (quinoline) xanthein (E104) etc.And the contained sodium alginate (water miscible alginate) of this prescription, alginic acid Sodium (water-insoluble alginate), and citric acid (organic carboxyl acid) be with help clarithromycin molten from.The content of sodium alginate and alginic acid Sodium differs greatly, and is difficult so want mix homogeneously.At United States Patent (USP) the 5th, 705, be 16: 1 to 1: 1 though mention sodium alginate in No. 190 to the ratio of alginic acid Sodium, its
Actual weight ratio in the XL ingot is 8: 1.If the two content of sodium alginate and alginic acid Sodium is adjusted to approaching, for example its ratio is 2: 1 or 1: 1, then for giving birth to the demand on the Journal of Sex Research such as bulk phase, and clarithromycin molten still slow a lot of from speed.
Summary of the invention
The purpose of this invention provides a sustained release type pharmaceutical compositions that contains difficult dissolubility principal agent (for example erythromycin derivatives) that confession is oral, in this compositions, only need use sodium alginate the sodium alginate that just is enough to replace in the Prior Art and is used and the compositions of alginic acid Sodium.Sodium alginate can be in order to forming the colloidal solution of stickiness, though and in the water soluble, be insoluble to pH less than in 3 the acid solution.So sodium alginate can protect erythromycin derivatives can not dissolve fast in gastric juice, thereby the stability of improvement erythromycin derivatives.Only not only can control the release of erythromycin derivatives, also can avoid the problem of the very difficult mix homogeneously of each component in manufacture process with sodium alginate.
On the other hand, the invention provides the oral sustained release type medicament that contains difficult dissolubility principal agent (for example erythromycin derivatives) of a kind of confession, and have the film clothing to coat.The present invention's medicament has the mouthfeel of improvement relatively more following with quick-release pharmaceutical compositions, and the side effect of the uncomfortable aspect of intestines and stomach is reduced to minimum.
Description of drawings
Fig. 1 illustrates
XL (with ORI representative) and the present invention's's (representing) clarithromycin sustained releasing type ingot molten in pH5.0 buffer solution from curve chart with PBF.
The specific embodiment
The invention provides the therapy of taking medicine a kind of every day once, it is to make the oral solid-state sustained release type pharmaceutical compositions that contains difficult dissolubility principal agent (for example erythromycin derivatives) of the patient who needs this treatment, its preferably dosage form be lozenge.
Erythromycin is a kind of macrolide antibiotic, and it is dissolved in ethanol and general organic solvent, but only is slightly soluble in the water; Extreme instability in the solution that is lower than pH 4.Erythromycin derivatives can comprise following all types: (1) acid-addition salts on the dimethylamino of desosamine, gluceptate for example, lactobionate and stearate; (2) ester on the OH of desosamine base, for example ethyl carbonate ester, ethyl succinate and propionic ester; And (3) clarithromycin etc.
The medicine that pharmaceutical compositions of the present invention can comprise known other uses to merge with erythromycin derivatives, as long as this kind combined treatment is for that need or favourable; And these and treatment gastritis, ulcer or the relevant other medicines of GERD disease (GERD), can be the medicine of antiulcer or gastritis, for example be selected from: suppress the chemical compound of stomachial secretion, as sulfalene azoles (sulfamethoxazole), Metronidazole (metronidazole), cimetidine (cimetidine), indapamide (indapamide), atenolol (atenolol), diazepam (diazepam), omeprazole (omeprazole), ranitidine (ranitidine), sucralfate (sucralfate) etc.; Or antacid such as magnesium hydroxide, aluminium hydroxide, sodium carbonate, Mai Likang (simethicone also claims dimethicone or likes every gift health) etc.
The content range of above-mentioned these medicines in pharmaceutical compositions can be 20% to 90% of entire combination thing or whole lozenge.For clarithromycin, preferable 40% to 80% of entire combination thing or the whole lozenge weight that can be of this content range.
Though the preferable system of the present invention uses sodium alginate, other cation, for example potassium ion, ammonium ion and other alkaline metal ions also can replace sodium ion and form water miscible alginic acid salt.The content range of water-soluble alginate can be 10% to 40% of entire combination thing or whole lozenge weight.
Required organic carboxyl acid is one to have enough effectiveness to create the acid of low pH value microenvironment in sustained release prescription of the present invention, just forms pH less than 7 microenvironment near the hydrolysis dosage form.This principal agent can be from 1: 1 to 6: 1 to the part by weight scope of acid, and with ratio the best of 4: 1.This acid is good with the aliphatic organic carboxyl acid that contains 3 to 20 carbon atoms, for example succinic acid, tartaric acid, malic acid, 1,3-propanedicarboxylic acid, maleic acid, glutamic acid, citric acid, mandelic acid etc., and with citric acid the best.
Sodium alginate in the sustained release prescription can reaction become alginic acid in the gastric juice of intestines and stomach, and alginic acid can be slightly soluble in the water, and can form thin film on the top layer of sustained release dosage form, and in order to the release of control medicine, this is because this film can be controlled the diffusion of medicine.The result is, water-insoluble alginate, and for example the alginic acid Sodium no longer needs to be used the release with the control clarithromycin.
Other composition as non-main constituent in sustained release prescription of the present invention comprises: pharmaceutically acceptable excipient, diluent, preservative agent (antiseptic), lubricant, antiseize paste, and through the pigment of permission.The present invention's dosage form also can and the control of drug release or material that correction have nothing to do coated at skin.
1. the granulation of sustained release type lozenge
All lozenge prescription system with as one of following as manufacture method and preparing.Clarithromycin, sodium alginate, lactose and hard ester acid are all by No. 40 screen clothes, remove any big caking, and the material that these have sieved mixed 20 minutes in mixer (Supermixer), slowly added polyvidon and citric acid solution again and formed suitable granule.These wet granules are by No. 16 screen clothes, and are 5～7% up to these granules with Ka Shi (Karl Fisher) moisture determination instrument mensuration moisture with 60 ℃ hot air drying.These dried granules by behind No. 20 screen clothes and lubricant on V-Mixer, mixed 2 minutes.
2. play ingot
To rotate Ingot pressing machine and install oval-shaped mould, respectively pastille dispensing thing I, II and III shown in following table one will be pressed into suitable thickness and brittleness.The composition of pastille dispensing thing is shown in following table I:
Table I
3. form membranaceous coating
Use a waterborne suspension to apply lozenge, this waterborne suspension comprises hydroxypropyl emthylcellulose, Polyethylene Glycol, sorbitol, titanium dioxide and pure water, and the result increases 2.5% of lozenge gross weight approximately.
Molten from degree research
1. molten from the degree test, according to American Pharmacopeia the 27th edition the 463rd page (2004)
0.1M sodium acetate buffer solution: its method for making is: gets sodium acetate trihydrate 13.61g, places 1 liter of volumetric flask, add water-soluble and be diluted to capacity, and mix homogeneously, adjusting its pH value with 0.1M acetic acid is 5.0.Solvent: state 0.1M sodium acetate buffer solution on the 900mL.
Device 2:50rpm
Sampling time point: 1st, 2,4,6,8,10,12,18 and 24 hours.
Mobile phase: its method for making is: the mixture (methanol is 650: 350 to the ratio of 0.067M potassium dihydrogen phosphate solution) of getting methanol and 0.067M potassium dihydrogen phosphate solution, adding phosphoric acid, to adjust its pH be 4.0, filter and degassing processing with aperture 0.5 μ m or thinner filter, can be adjusted again in case of necessity.
Standard solution: its method for making is: the warp of getting about 27mg is the clarithromycin of weighing accurately, in the 50mL volumetric bottle with 40mL as above-mentioned dissolution with solvents, if need to shake and the ultrasound vibration, to guarantee that dissolving fully., filter with aperture 0.5 μ m or thinner filter behind the mixing to quantitatively with solvent dilution.Get filtrate as standard solution.The every mL of this solution contains the clarithromycin of the 54 μ g that have an appointment.
Chromatographic apparatus: liquid phase chromatography device, tool wavelength 210nm detector, and 4.6mm * 15cm Inertsil ODS-2 chromatography pipe: 5 μ m, chromatography pipe temperature is maintained at about 50 ℃, the about 1mL of mobile phase flow velocity per minute.With standard solution be subjected to test sample solution to carry out chromatography, write down its reaction: by the measured tubing string efficient of clarithromycin crest value, it is for being not less than 750 number of theoretical plates, its crest factor of smearing also is not more than 2 for being not less than 0.9; And the relative standard deviation who repeats injection is for being not more than 2.0%.
Algoscopy: get standard solution and be subjected to the test sample solution (solution that this is formed through quantitative mobile phase dilution by the sample that will obtain by test sample solution, initial every mL contains the clarithromycin of the 54 μ g that have an appointment) equivalent (about 20～50 μ L), respectively implanted layer analysis apparatus chromatography it, write down its tomographic map, survey each main crest of meter.According to following formula calculate clarithromycin in dissolving-separating test molten from amount (unit is μ g):
900(CD)(r
u/r
s)
Wherein
C: the every mL of standard solution contains the μ g number of clarithromycin
D: the suitable extension rate when preparation is subjected to test sample solution
r
uAnd r
s: the crest value that is respectively inspection product solution and standard solution main constituent
2. molten from degree result and discussion
Respectively to derive from Abbott Laboratories Ltd.'s (Queenborough, Kent, ME11 5EL, Britain)
The XL ingot (clarithromycin, 500mg) and each 6 of sustained releasing type clarithromycin lozenge of the present invention, as above-mentioned 0.1M sodium acetate buffer solution in, carry out as above-mentioned molten from degree research, its molten condition from the degree test as mentioned above.And both show it from the molten of separate sources lozenge from the following Table II of degree result.
The molten of Table II clarithromycin lozenge studied from degree
The present invention: the present invention's sustained releasing type clarithromycin lozenge
The two molten from curve as shown in Figure 1, this figure is
XL (ORI) and the present invention's (PBF) clarithromycin sustained releasing type ingot molten from curve chart.
Table III---in six tests, each
XL lozenge (ORI) molten from the result, meansigma methods is with (ave) expression, and the relative standard deviation represents with (RSD)
Table IV---in six tests, each the present invention's clarithromycin sustained releasing type lozenge (PBF) molten from the result, meansigma methods is with (ave) expression, and the relative standard deviation represents with (RSD)
The two molten from curve as shown in Figure 1, this figure is
XL lozenge (ORI) and the present invention's (PBF) clarithromycin sustained releasing type lozenge molten from curve chart, the two molten at each time point as seen from Figure 1 from very approaching of degree, only except the 18 hour molten from degree differed 5.46% (that is, 81.93%-76.47%=5.46%), other each point is all less than 5%, therefore the two in clinical trial, the body equality of may making a living each other.
In addition,
It is molten from the result that XL lozenge and the present invention's clarithromycin continues each time point of each ingot of type lozenge, shown in Table III and Table IV, for
In six tests of XL lozenge, in the relative standard deviation (RSD) of each time point between 1.16% and 14.37%, and in six tests for the present invention's clarithromycin sustained releasing type lozenge, in the relative standard deviation (RSD) of each time point between 0.92% and 10.49%.Therefore,
The average relative standard deviation of XL lozenge and the present invention's clarithromycin sustained releasing type lozenge is respectively 4.71% and 2.98%.This has represented that a molten to each other release attitude of clarithromycin sustained releasing type lozenge is more similar more than the present invention, and shows by contrast, and is a plurality of
The molten to each other release attitude of XL lozenge is dissimilar.This advantage system reviews because use sodium alginate among the present invention
Use the compositions of sodium alginate and alginic acid Sodium in the XL lozenge, and
These two kinds of different alginate can cause more difficult blended problem in the manufacture process of XL lozenge.
Advantage of the present invention
A. the present invention shows for can comparatively reducing than easy operating and cost relatively descending for the 5th, 705, No. 190 with the United States Patent (USP) that uses two kinds of different alginate to prepare sustained releasing type lozenge.
B. at the sodium alginate of the present invention's sustained release prescription, in the gastric juice of intestines and stomach, can reaction become alginic acid, and alginic acid can be slightly soluble in the water, and can form thin film on the top layer of sustained release dosage form, in order to the release of control medicine, this is because this film can be controlled the diffusion of medicine.
C. as can be known, by the data of Table II the present invention's lozenge with
XL lozenge relatively down, it is molten not to have significant difference from degree; Yet by Table III and IV as can be known, the present inventor has obviously less average relative standard deviation (RSD), can learn that therefore a molten to each other release attitude of clarithromycin sustained releasing type lozenge is more similar more than the present invention, and show by contrast, and is a plurality of
The molten to each other release attitude of XL lozenge is dissimilar.
Claims (9)
1. one kind is fit to oral sustained releasing type solid pharmaceutical compositions, and it comprises;
The principal agent of effective dose at least a treatment, it has the character in the water of being insoluble in, and it is a macrolide antibiotic;
A kind of alginate; And
A kind of organic carboxyl acid can help the dissolving of this principal agent;
Wherein, this principal agent is between 1: 1 and 6: 1 to the part by weight scope of this organic carboxyl acid,
Described alginate only are a kind of water-soluble alginate, and described compositions does not contain water-insoluble alginate.
2. pharmaceutical compositions according to claim 1 is characterized in that, it is the form of lozenge.
3. pharmaceutical compositions according to claim 1 is characterized in that, it throws clothes one dosage form that takes second place every day for being applicable to.
4. pharmaceutical compositions according to claim 1 is characterized in that, this macrolide antibiotic is a clarithromycin.
5. pharmaceutical compositions according to claim 1 is characterized in that, this water-soluble alginate is a sodium alginate.
6. pharmaceutical compositions according to claim 1 is characterized in that, this organic carboxyl acid is selected from succinic acid, tartaric acid, maleic acid, 1,3-propanedicarboxylic acid, malic acid, glutamine acid, citric acid and mandelic acid.
7. pharmaceutical compositions according to claim 6 is characterized in that, this organic carboxyl acid is a citric acid.
8. pharmaceutical compositions according to claim 5 is characterized in that, sodium alginate is 1: 2 to the part by weight of principal agent.
9. pharmaceutical compositions according to claim 1, it is characterized in that described alginate are sodium alginate, principal agent is a clarithromycin, organic carboxyl acid is a citric acid, and this pharmaceutical composition comprises 500 milligrams clarithromycin, 200 to 400 milligrams sodium alginate, and 105 to 130 milligrams citric acid.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB200410043476XA CN100435847C (en) | 2004-05-13 | 2004-05-13 | Continuing release recipe of containing infusible basic remedy |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200410043476XA CN100435847C (en) | 2004-05-13 | 2004-05-13 | Continuing release recipe of containing infusible basic remedy |
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| CN1695739A CN1695739A (en) | 2005-11-16 |
| CN100435847C true CN100435847C (en) | 2008-11-26 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1205629A (en) * | 1995-12-19 | 1999-01-20 | 艾博特公司 | Controlled release formulation for poorly soluble basic drugs |
| CN1316899A (en) * | 1998-07-31 | 2001-10-10 | 大塚制药株式会社 | Pharmaceutical composition having improved taste |
| CN1415305A (en) * | 2002-11-25 | 2003-05-07 | 沈阳药科大学 | Sustained release preparation of roxithromycin |
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2004
- 2004-05-13 CN CNB200410043476XA patent/CN100435847C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1205629A (en) * | 1995-12-19 | 1999-01-20 | 艾博特公司 | Controlled release formulation for poorly soluble basic drugs |
| CN1316899A (en) * | 1998-07-31 | 2001-10-10 | 大塚制药株式会社 | Pharmaceutical composition having improved taste |
| CN1415305A (en) * | 2002-11-25 | 2003-05-07 | 沈阳药科大学 | Sustained release preparation of roxithromycin |
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