CN100435847C - Sustained release formulation containing poorly soluble principal drug - Google Patents

Abstract

The present invention provides a sustained-release oral pharmaceutical composition suitable for daily administration therapy, comprising at least one poorly soluble main drug (e.g., erythromycin derivative). The pharmaceutical composition comprises the main drug, a water-soluble alginate, and an organic carboxylic acid. The present invention particularly provides a controlled-release tablet of clarithromycin.

Description

Sustained release formula containing poorly soluble main drug

technical field

The present invention relates to an oral sustained-release formulation of a poorly soluble main drug, such as an erythromycin derivative, which can be digested in gastrointestinal fluid. In particular, the present invention relates to a pharmaceutical composition of clarithromycin which can be administered in the form of one tablet per day.

Background technique

Erythromycin and its derivatives are antibacterial agents, they have a wide range of antibacterial activity, and some of the same antibacterial activity as penicillin, especially for Gram-positive cocci, such as enterococcus, hemolytic streptococcus group A , pneumococcus and staphylococcus are effective. The usual dosage is to take 2-4 times a day for 10-14 consecutive days. For ambulatory patients, taking 2 to 4 times a day may cause inconvenience, or forget to take; therefore, it is better to reduce the number of daily doses. Especially for non-hospitalized patients, the solid-state sustained-release formulation can reduce the number of doses. The sustained-release formula is to keep the blood concentration of the drug in a stable state relative to time, so that patients who take 2-4 times a day can avoid drug overdose when taking the next tablet.

The use of alginate gels for the preparation of controlled release tablets is known. A water-soluble alginate, such as sodium alginate, can be reacted with a calcium salt so that the alginate is converted into a water-insoluble sodium alginate-calcium gel. The controlled-release properties of alginate gel can be changed by changing the molecular weight of alginate, the content of alginate, the type of multivalent cations and cross-linking agents, and (or) the content of cations in alginate. US Patent No. 4,842,866 discloses the use of sodium alginate and sodium-calcium alginate to prepare solid controlled release dosage forms.

The patented technology mentioned above cannot be applied to the formulation containing the main drug with very low water solubility, for example, the formulation made of clarithromycin and alginate, its dissolution is too slow and its in vivo test results are limited. Bioavailability is not reproducible. For drugs with very low water solubility, alginate can be used as a matrix and organic acids can be added to make solid controlled release dosage forms. U.S. Patent No. 5,705,190 (which is equivalent to Taiwan Patent No. 429,154) discloses a controlled release dosage form containing water-soluble alginates, alginate complexes and organic carboxylic acids (which can promote the dissolution of active ingredients) . An example of an active ingredient is clarithromycin, which is readily soluble in gastric juices and in the upper part of the small intestine (pH 5.0), where clarithromycin is most likely to be absorbed; (pH 6 to 8) is not easy to dissolve, so in order to increase the solubility in this part, citric acid is used in the formula. In the oral pharmaceutical composition applied for in U.S. Patent No. 5,705,190, the weight ratio of sodium alginate to sodium alginate-calcium is about 16:1 to 1:1, and the molar ratio of organic acid (such as citric acid) to the main drug It is 1:1.

In US Patent No. 5,705,190, the solid controlled release pharmaceutical composition comprises sodium alginate, sodium alginate-calcium and organic carboxylic acid (such as citric acid). However, this formulation cannot resolve or reduce side effects related to gastrointestinal discomfort, including symptoms such as nausea, vomiting, and dysgeusia. In order to overcome the above-mentioned problems, an improved controlled-release dosage form containing a poorly soluble main drug (such as erythromycin) has been developed, as described in US Patent No. 6,010,718. These formulations contain pharmaceutically acceptable polymers, such as hydroxypropyl methylcellulose, to improve the taste of the immediate release dosage form and reduce gastrointestinal side effects. U.S. Patent No. 6,551,661B1 is similar to U.S. Patent No. 6,010,718, but the former includes more research results on the side effects of the gastrointestinal tract of patients, and it is proved that patients taking clarithromycin sustained-release formulations are significantly less likely to suffer from gastrointestinal side effects However, the drug was discontinued, and the gastrointestinal side effects occurred in these patients were significantly less serious.

XL锭(Abbott Laboratories Ltd.，Queenborough，Kent，ME11 5EL，英国，克拉霉素持续释放锭)含有500毫克的克拉霉素和其它非活性组份如：柠檬酸、藻酸钠、藻酸钠-钙、乳糖、聚乙烯吡咯酮(povidone)、滑石粉、硬脂酸、硬脂酸镁、羟丙基甲基纤维素、丙二醇、二氧化钛(E1711)、山梨酸、喹啉(quinoline)黄色色素(E104)等。而此配方所含之藻酸钠(水溶性的藻酸盐)、藻酸钠-钙(水不溶性的藻酸盐)、及柠檬酸(有机羧酸)系用来帮助克拉霉素溶离。藻酸钠与藻酸钠-钙的含量相差悬殊，所以要混合均匀是困难的。在美国专利第5,705,190号中虽提及藻酸钠对藻酸钠-钙的比是16∶1到1∶1，但其在

XL锭中之实际重量比为8∶1。若将藻酸钠和藻酸钠-钙二者的含量调整至接近，例如其比例为2∶1或1∶1，则对生体相等性研究上之需求而言，克拉霉素之溶离速率仍然慢很多。As disclosed in U.S. Patent No. 5,705,190,

XL tablets (Abbott Laboratories Ltd., Queenborough, Kent, ME11 5EL, UK, clarithromycin sustained release tablets) contain 500 mg of clarithromycin and other inactive ingredients such as: citric acid, sodium alginate, sodium alginate- Calcium, lactose, povidone, talc, stearic acid, magnesium stearate, hydroxypropyl methylcellulose, propylene glycol, titanium dioxide (E1711), sorbic acid, quinoline yellow coloring ( E104) etc. The sodium alginate (water-soluble alginate), sodium-calcium alginate (water-insoluble alginate), and citric acid (organic carboxylic acid) contained in this formula are used to help clarithromycin dissolve. The content of sodium alginate and sodium alginate-calcium is very different, so it is difficult to mix evenly. Although it is mentioned in U.S. Patent No. 5,705,190 that the ratio of sodium alginate to sodium alginate-calcium is 16:1 to 1:1, it is

The actual weight ratio in XL ingots is 8:1. If the contents of sodium alginate and sodium alginate-calcium are adjusted to be close, for example, the ratio is 2:1 or 1:1, the dissolution rate of clarithromycin Still a lot slower.

Contents of the invention

The purpose of this invention is to provide a controlled-release pharmaceutical composition containing a poorly soluble main drug (such as erythromycin derivatives) for oral administration. In this composition, only sodium alginate is needed to replace the previous art. Compositions of sodium alginate and sodium-calcium alginate used. Sodium alginate can be used to form a viscous colloidal solution, and although soluble in water, it is insoluble in acidic solutions with a pH less than 3. So sodium alginate can protect erythromycin derivatives from rapidly dissolving in gastric juice, thus improving the stability of erythromycin derivatives. Only using sodium alginate can not only control the release of erythromycin derivatives, but also avoid the problem that the components are difficult to mix uniformly during the manufacturing process.

In another aspect, the present invention provides a controlled-release medicament containing a poorly soluble main drug (such as erythromycin derivatives) for oral administration and coated with a film coating. Compared with the rapid-release pharmaceutical composition, the medicament of the present invention has improved taste, and the side effects of gastrointestinal discomfort are minimized.

Description of drawings

XL(以ORI代表)和本发明(以PBF代表)之克拉霉素持续释放型锭在pH5.0缓冲溶液中的溶离曲线图。Figure 1 shows

Dissolution curves of clarithromycin sustained-release tablets of XL (represented by ORI) and the present invention (represented by PBF) in pH 5.0 buffer solution.

Detailed ways

The present invention provides a therapy for taking medicine once a day, which is to make the patient in need of the therapy orally contain a solid-state controlled-release pharmaceutical composition containing a poorly soluble main drug (such as erythromycin derivatives), and its preferred dosage form is Lozenges.

Erythromycin is a macrolide antibiotic, which is soluble in alcohol and common organic solvents, but only slightly soluble in water; it is extremely unstable in solutions below pH 4. Erythromycin derivatives can include the following types: (1) acid addition salts on the dimethylamino group of deoxysugaramine, such as glucoheptonate, lactobionate and stearate; (2) ) esters on the OH group of deoxysugaramine, such as ethyl carbonate, ethyl succinate and propionate; and (3) clarithromycin, etc.

The pharmaceutical composition of the present invention may contain other known drugs to be used in combination with the erythromycin derivatives, as long as such combined treatment is needed or beneficial; and these are related to the treatment of gastritis, ulcer or gastroesophageal reflux disease (GERD) The other related drugs can be anti-ulcer or anti-gastritis drugs, for example, selected from: compounds that inhibit gastric secretion, such as sulfamethoxazole, metronidazole, cimetidine, inda Indapamide, atenolol, diazepam, omeprazole, ranitidine, sucralfate, etc.; or antacids such as Magnesium hydroxide, aluminum hydroxide, sodium carbonate, simethicone (also known as simethicone or simethicone), etc.

The content range of the above-mentioned drugs in the pharmaceutical composition may be 20% to 90% of the whole composition or the whole tablet. For clarithromycin, the content range is preferably 40% to 80% by weight of the whole composition or the whole tablet.

Although sodium alginate is preferably used in the present invention, other cations, such as potassium ions, ammonium ions and other basic metal ions, can also replace sodium ions to form water-soluble alginates. The content of water-soluble alginate can range from 10% to 40% by weight of the whole composition or the whole tablet.

The desired organic carboxylic acid in the controlled release formulations of the present invention is one that is sufficiently effective to create a low pH microenvironment, ie, a pH less than 7 microenvironment in the vicinity of the hydrolyzed dosage form. The weight ratio of the main ingredient to the acid can range from 1:1 to 6:1, and the ratio of 4:1 is the best. The acid is preferably an aliphatic organic carboxylic acid containing 3 to 20 carbon atoms, such as succinic acid, tartaric acid, malic acid, glutaric acid, maleic acid, glutamic acid, citric acid, mandelic acid, etc., and Citric acid is the best.

The sodium alginate in the controlled-release formula will react into alginic acid in the gastric juice of the gastrointestinal tract, and the alginic acid is slightly soluble in water, and will form a film on the surface of the controlled-release dosage form to control the release of the drug. This is because the membrane controls the diffusion of the drug. As a result, water-insoluble alginates, such as sodium-calcium alginate, no longer need to be used to control the release of clarithromycin.

Other ingredients that are not main ingredients in the controlled-release formulation of the present invention include: pharmaceutically acceptable excipients, diluents, preservatives (preservatives), lubricants, slip agents, and approved pigments. The dosage forms of the present invention may also be coated on the outer layer with substances not related to the control or modification of drug release.

Example 1

1. Granulation of controlled release tablets

All lozenge formulations were prepared by the general method of manufacture as described below. The clarithromycin, sodium alginate, lactose, and stearic acid were all passed through a No. 40 sieve to remove any large lumps, and the sieved material was mixed in a Supermixer for 20 minutes, then slowly A solution of povidone and citric acid was added to form suitable granules. These wet granules pass through a No. 16 sieve, and are dried with hot air at 60° C. until the granules have a moisture content of 5-7% as measured by a Karl Fisher moisture analyzer. After passing through a No. 20 screen, the dried granules were mixed with lubricant on a V-blender for 2 minutes.

2. Ingot making

The rotary tablet machine was equipped with an oval mold, and the tablet formulations I, II and III shown in Table 1 below were respectively pressed into suitable thickness and crispness. The composition of the lozenge formulation is shown in Table I below:

Table I

3. Form a film-like coating

The tablets were coated with an aqueous suspension comprising hydroxypropylmethylcellulose, polyethylene glycol, sorbitol, titanium dioxide and purified water, resulting in an increase of about 2.5% of the total weight of the tablets.

Example 2

Solubility studies

1. Solubility test, according to page 463 of the 27th edition of the United States Pharmacopoeia (2004)

0.1M sodium acetate buffer solution: the preparation method is as follows: take 13.61g of sodium acetate trihydrate, put it in a 1-liter volumetric flask, add water to dissolve it and dilute to volume, mix well, and adjust its pH value to 5.0 with 0.1M acetic acid. Solvent: 900 mL of the above 0.1 M sodium acetate buffer solution.

Device 2: 50rpm

Sampling time points: 1st, 2nd, 4th, 6th, 8th, 10th, 12th, 18th and 24th hours.

Mobile phase: Its preparation method is: take a mixture of methanol and 0.067M potassium dihydrogen phosphate solution (the ratio of methanol to 0.067M potassium dihydrogen phosphate solution is 650:350), add phosphoric acid to adjust its pH to 4.0, and use a pore size of 0.5 μm or a finer filter and degassed, and adjusted if necessary.

Standard solution: The preparation method is as follows: take about 27mg of clarithromycin which has been accurately weighed, and dissolve it with 40mL of the above-mentioned solvent in a 50mL quantitative bottle. If necessary, shake and ultrasonically oscillate to ensure complete dissolution. Dilute to quantitative with a solvent, mix well and filter with a filter with a pore size of 0.5 μm or finer. Take the filtrate as the standard solution. This solution contained approximately 54 μg of clarithromycin per mL.

Chromatography device: liquid chromatography device, with a detector with a wavelength of 210nm, and a 4.6mm×15cm Inertsil ODS-2 chromatography tube: 5μm, the temperature of the chromatography tube is kept at about 50°C, and the flow rate of the mobile phase is about 1mL per minute. Perform chromatography on the standard solution and the test solution, and record the reaction: the column efficiency measured by the clarithromycin wave peak is not less than 750 theoretical plates, and the peak tailing factor is not less than 0.9. Not greater than 2; and the relative standard deviation of repeated injections is not greater than 2.0%.

Determination method: take the standard solution and the test solution (the test solution is a solution formed by diluting the obtained sample with a quantitative mobile phase, and initially contains about 54 μg of clarithromycin per mL) (about 20-50 μL), respectively injected into the chromatographic device for chromatography, recorded the chromatogram, and measured the main peaks. Calculate the amount of clarithromycin dissolved in the dissolution test (in μg) according to the following formula:

900(CD)(r _u /r _s )

in

C: μg of clarithromycin per mL of the standard solution

D: Appropriate dilution factor when preparing the test product solution

r _u and r _s : the peak values of the main components of the test solution and the standard solution, respectively

2. Dissolution Results and Discussion

XL锭(克拉霉素，500mg)和本发明的持续释放型克拉霉素锭剂各6粒，在如上述之0.1M醋酸钠缓冲溶液中，进行如上述之溶离度研究，其溶离度试验的条件如上所述。而两者来自不同来源锭剂之溶离度结果如下表II示之。Respectively obtained from Abbott Laboratories Ltd. (Queenborough, Kent, ME11 5EL, UK)

Each of XL tablets (clarithromycin, 500mg) and sustained-release clarithromycin lozenges of the present invention has 6 capsules. In the above-mentioned 0.1M sodium acetate buffer solution, the above-mentioned solubility research is carried out. The conditions of the test are as described above. The results of the solubility of the two tablets from different sources are shown in Table II below.

Table II Dissolution studies of clarithromycin lozenges

The present invention: sustained-release clarithromycin tablet of the present invention

XL(ORI)和本发明(PBF)之克拉霉素持续释放型锭的溶离曲线图。The dissociation curves of the two are shown in Figure 1, which is

Dissolution profiles of clarithromycin sustained-release tablets of XL (ORI) and the present invention (PBF).

Table III --- Among the six tests, each Dissolution results of XL lozenges (ORI), the average value is expressed as (ave), and the relative standard deviation is expressed as (RSD)

Table IV --- in six tests, the dissolution results of each clarithromycin sustained-release lozenge (PBF) of the present invention, the average value is expressed in (ave), and the relative standard deviation is expressed in (RSD)

XL锭剂(ORI)和本发明(PBF)之克拉霉素持续释放型锭剂的溶离曲线图，由图1可见二者在各时间点的溶离度非常的接近，只除了在第十八小时之溶离度相差有5.46％(亦即，81.93％-76.47％＝5.46％)外，其它各点均小于5％，因此二者在临床试验中，可能彼此为生体相等性的。The dissociation curves of the two are shown in Figure 1, which is

The dissolution curves of the clarithromycin sustained-release tablet of the XL lozenge (ORI) and the present invention (PBF), as can be seen from Fig. 1, the dissolution rate of the two at each time point is very close, except at the tenth Except for the difference of 5.46% (that is, 81.93%-76.47%=5.46%) in the eight-hour solubility, the other points are all less than 5%. Therefore, the two may be biologically equivalent to each other in clinical trials.

XL锭剂和本发明之克拉霉素持续型锭剂的每一锭的各个时间点溶离结果，如表III和表IV所示，在对于

XL锭剂之六次测试中，在每个时间点的相对标准误差(RSD)在1.16％与14.37％之间，而对于本发明之克拉霉素持续释放型锭剂之六次测试中，在每个时间点的相对标准误差(RSD)在0.92％与10.49％之间。因此，

XL锭剂和本发明之克拉霉素持续释放型锭剂的平均相对标准误差分别是4.71％和2.98％。此表示了本发明之多个克拉霉素持续释放型锭剂彼此间之溶离型态较相似，而相比之下显出，多个

XL锭剂彼此间之溶离型态较不相似。此项优点系因为本发明中使用藻酸钠，反观

XL锭剂中使用藻酸钠和藻酸钠-钙之组合物，而在

XL锭剂之制造过程中该两种不同的藻酸盐会引起较难混合的问题。also,

Dissolution results at each time point of XL lozenge and clarithromycin continuous lozenge of the present invention, as shown in table III and table IV, for

In the six tests of the XL tablet, the relative standard deviation (RSD) at each time point was between 1.16% and 14.37%, while in the six tests of the clarithromycin sustained-release tablet of the present invention, in The relative standard deviation (RSD) for each time point was between 0.92% and 10.49%. therefore,

The mean relative standard errors for the XL tablet and the clarithromycin sustained release tablet of the present invention were 4.71% and 2.98%, respectively. This shows that the dissolution patterns of multiple clarithromycin sustained-release tablets of the present invention are similar to each other, while in contrast, multiple

The dissolution profiles of the XL lozenges were less similar to each other. This advantage is because sodium alginate is used in the present invention, on the other hand

Sodium alginate and a combination of sodium alginate-calcium were used in XL lozenges, whereas in

The two different alginates caused more difficult mixing problems during the manufacture of the XL lozenges.

Advantages of the invention

A. Compared with US Patent No. 5,705,190, which uses two different alginates to prepare sustained-release lozenges, the present invention is easier to operate and lower in cost.

B. The sodium alginate in the controlled-release formulation of the present invention will react into alginic acid in the gastric juice of the gastrointestinal tract, and alginic acid is slightly soluble in water, and will form a thin film on the surface of the controlled-release dosage form for use in The release of the drug is controlled because the membrane controls the diffusion of the drug.

XL锭剂比较下，其溶离度并没有显著的差异；然而，由表III与IV可知，本发明者有明显较小的平均相对标准误差(RSD)，因此可得知本发明之多个克拉霉素持续释放型锭剂彼此间之溶离型态较相似，而相比之下显出，多个

XL锭剂彼此间之溶离型态较不相似。C. Known from the data of table II, lozenge of the present invention is in and

Compared with XL lozenges, there is no significant difference in its dissolution rate; however, as can be seen from Tables III and IV, the inventors have significantly smaller average relative standard deviation (RSD), so it can be known that the present invention has multiple The dissolution profiles of clarithromycin sustained-release lozenges were relatively similar to each other, while in contrast multiple

The dissolution profiles of the XL lozenges were less similar to each other.

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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