Extended release tablet of clarithromycin

Formulations of erythromycin derivatives

Long-term release

Full description

Background of the invention

The present invention relates to pharmaceutical compositions of erythromycin derivatives with extended release of an active compound in the gastrointestinal environment. It relates in particular to pharmaceutical formulations of clarithromycin given once daily for

Oral route.

Erythromycin and its derivatives are known for their antibacterial activity against a number of organisms or their effectiveness in a number of indications and are usually given in the form of immediate release (IR) compositions, two or three times daily, for a period ranging from 10-14 days. These compounds have a bitter taste. In particular, 6-O-methoxyeryrthromycin AA (clarithromycin) has a bitter metallic taste that can lead to a poor response to the regimen or the choice of another, potentially less effective, therapeutic agent.

One way to improve the potential non-compliance of the system is to develop controlled release solid preparations containing these erythromycin derivatives in an alginate matrix containing water-soluble alginate and a complex salt of acid.

Alginic acid has one cation that produces a soluble alginate salt and another cation that alone produces an insoluble alginate salt. These compositions are described in US Patent 4,842,866, issued on June 27, 1989. However, in vivo animal studies have shown that a bioavailable controlled-release formulation cannot be obtained and can be recovered using alginates or other monolithic hydrogel tablets.

To overcome some of the problems associated with the compositions described in US Patent 4,842,866, improved controlled-release compositions of poorly soluble basic drugs such as erythromycin derivatives, including clarithromycin, have been developed and are described in the pending US patent application of the present patent applicant. , serial number 08/574.877, filed on December 19, 1995. The compositions described in this patent application contain a poorly soluble base drug and citric acid in an alginate matrix. The formulations are administered once daily and aim to increase the bioavailability of the active ingredient so that they are bioequivalent to current immediate-release formulations, which are administered twice daily. However, these controlled-release formulations are not intended to reduce adverse effects related to gastrointestinal (GI) disorders, including nausea, vomiting, and a phenomenon termed taste peversion.

One way to combat taste impairment is to develop acceptable palatable liquid oral dosage forms of these drugs as described in US Patent 4,808,411 issued on February 28, 1989. However, these formulations are given twice daily for 10-14 days and do not experience frequency, duration of administration, or adverse gastrointestinal disturbance effects. Hence, there is still a need to develop a pharmaceutical formulation that reduces the adverse effects described above and ensures a degree of safety

Plasma drug concentration control is equivalent to or better than currently used tablet and liquid immediate-release (IR) formulations. General description of the invention

Extended-release (ER) compositions of the present invention containing a pharmaceutically acceptable polymer have been found to give clarithromycin ER in vivo when given once daily. Maximum concentrations (Cmax) of clarithromycin in plasma are statistically significantly lower than those for the twice-daily immediate-release formulation, maintaining the area under the plasma concentration-time curve (AUC) and the lowest 24-hour plasma concentration. . In contrast, the Cmax values for the controlled-release compositions described in pending US patent application serial number 08/574,877, filed on December 19, 1995, are not statistically significantly different from those values for the immediate-release composition. While the AUC is maintained over 24 hours, the Cmax value is statistically significantly lower. Great for controlled-release formulations to immediate-release formulations. The formulations of the invention amazingly reduced the incidence of taste spoilage by two to three times that of the immediate-release formulation.

In one aspect, the present invention relates to a pharmaceutical composition for the long-term release of an erythromycin derivative into the gastrointestinal tract, containing the erythromycin derivative and a pharmaceutically acceptable polymer, such that the composition, when administered orally, induces a statistically lower mean fluctuation index in plasma. . Significantly greater than that induced by the immediate-release formulation of the erythromycin derivative while maintaining bioavailability substantially equivalent to that produced by the immediate-release formulation of the erythromycin derivative.

In another aspect, the present invention relates to a pharmaceutical composition for the long-term release of an erythromycin derivative into the gastrointestinal tract, containing a derivative

Erythromycin and a pharmaceutically acceptable polymer, such that the maximum peak concentrations of the erythromycin derivative, when administered orally, are statistically significantly lower than those produced by an immediate-release pharmaceutical formulation, and the area under the concentration-time curve and the lowest plasma concentration are substantially equivalent to those Resulting from an immediate-release pharmaceutical formulation.

In yet another aspect, the present invention relates to a method of using a long-acting release pharmaceutical composition, containing an erythromycin derivative and a pharmaceutically acceptable polymer, including administering the composition in an effective amount to treat mammals from a bacterial infection, thus maintaining an area under the concentration-time curve equivalent to For those resulting from an immediate-release pharmaceutical formulation of an erythromycin derivative

In yet another respect, the present invention relates to a long-release pharmaceutical composition containing an erythromycin derivative and a pharmaceutically acceptable polymer, wherein the composition has an improved taste profile relative to the immediate-release composition. Brief explanation of fees

Figure 1: shows the average plasma concentration-time profile in vivo after a dose

One single dose of three 500 milligram (mg) extended-release tablets containing clarithromycin and 10% or

20% or 30% by weight, respectively, of hydroxypropylmethyl

Cellulose K 100 LV hydroxypropylmethyl cellulose K 100 LV,

Compared to the reference clarithromycin 500 mg immediate-release tablet.

Figure 2: shows the average plasma concentration-time profile in vivo after several doses

Of each of the two extended-release tablets containing 10%, or

20% by weight, by order, of hydroxypropyl methylcellulose K100LV

hydroxypropylmethyl cellulose K 100 LV compared to the reference tablet

Immediate release. Dosage forms include two 500 mg extended-release tablets taken once daily or one clarithromycin 500 mg immediate-release tablet taken every 12 hours, in order, taken for three days with food.

Figure 3: shows the average plasma concentration-time profile in vivo after several doses

of clarithromycin 1000 mg (not an example of the invention)

It is taken once a day and 500 mg immediate-release is taken twice a day.

Detailed description

When used in this statement, “500 mg” or “1,000 mg” means the concentration of the tablet composition containing 500 mg clarithromycin, or the dose given as 2 x 500 mg clarithromycin, respectively.

When used in this statement, the term “Cmax” means the maximum concentration of the erythromycin derivative in plasma, which is produced by taking the immediate-release composition of the invention or the comparator.

When used in this statement, the term “Cmin” means the minimum concentration of the erythromycin derivative in plasma that would result from administration of the immediate-release composition of the invention or the comparative composition.

When used in this statement, the term “Cavg” means the average concentration over 24 hours.

When used in this statement, the term &Tmax means the time required to observe the maximum concentration in plasma.

The term &auc& when used in this statement means the area under the plasma concentration-time curve, as calculated using the trapezoidal rule over the entire 24 hours for all formulations.

When used in this statement, the degree of fluctuation (DFL) is expressed.

B: DFL=(Cmax- Cmin)/ Cavg.

When used in this statement, the term “erythromycin derivative” means erythromycin that does not contain substituent groups, or contains conventional substituent groups, in organic synthesis, rather than a hydrogen atom for hydroxy groups and/or a hydroxy group. A methyl methyl group of 3'-dimethylamino, prepared according to the conventional method.

The term “pharmaceutical acceptable” when used in this statement means those compounds that are suitable for use, in accordance with sound medical judgment, such that they come into contact with the tissues of humans and lower animals without causing toxicity, irritation, allergic response, and the like, with harmony. With a reasonable benefit/risk ratio, they are effective in their desired uses in chemotherapy and prophylaxis prophylaxis for antimicrobial infections.

The term “adverse effects” when used in this statement means those physiological effects of various systems in the body, including the cardiovascular systems, the nervous system, the digestive system, and the body as a whole, that cause pain and discomfort to the person.

The term “taste deterioration” when used in this statement means the bitter, metallic taste commonly associated with erythromycin derivatives, in particular, clarithromycin.

clarithromycin.

The pharmaceutical composition according to the invention contains a pharmaceutically active compound and a pharmaceutically acceptable polymer. The pharmaceutically active compound is an erythromycin derivative. Preferably, the erythromycin derivative is 6-O-methoxyerythromycin AA, which

Known as clarithromycin. The amount of the erythromycin derivative varies from about 45% to about 60% by weight of the composition. Preferably, the composition contains approximately 50% by weight of the erythromycin derivative.

The pharmaceutically acceptable polymer shall be a water-soluble hydrophilic polymer chosen from the class consisting of polyvinylpyrrolidine, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, and copolymers from vinyl acetate/crotonic acid, methacrylic acid copolymers, Copolymers of maleic anhydride/methyl vinyl ether and derivatives and mixtures of these compounds. Preferably, the polymer should be chosen from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or methyl cellulose. Better yet, the polymer should be hydroxypropylmethyl cellulose. Most preferably, the polymer is hydroxypropylmethyl cellulose with a low viscosity, with a viscosity ranging from about 50 centipoises (cps) to about 200 centipoises. The most preferable low-viscosity polymer is hydroxypropylmethyl cellulose with a viscosity of about 100 centipoise, commercially available under the trade name Methocel™ K LV 100 from Dow Chemical Company.

The amount of polymer in the composition usually varies from about 5% to about 50% by weight

Installation. Preferably, the amount of polymers varies from about 10% to about 35% by weight of the composition. And the most preferred. The amount of polymer varies from about 10% to about 30% by weight of the composition.

The composition according to this invention additionally contains excipients and/or pharmaceutically acceptable fillers and extenders, lactose, starches, glucose, sucrose, mannitol, silicic acid, lubricants such as talc, stearates. Calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures of these substances.

The amount of lubricant typically varies from about 0.5% to about 10% by weight of the composition. Preferably, the lubricants used are magnesium stearate and talc in total amounts ranging from. About 1% to about 4% by weight of the composition. The amount of fillers and extenders varies from about 10% to about 40% by weight of the composition.

A particularly favorable composition for long-term release of the active compound contains:

About 500 mg of clarithromycin; And

100 to 300 mg of Methocel K 100 LV

LV.

The compositions are usually prepared by dry blending the polymer, filler, erythromycin derivative, and other excipients, then granulating the mixture using water until a suitable granulation is obtained. Granulation is performed by methods known in technology. The wet granules are dried in a fluid bed dryer, screened and ground to a suitable size. Lubricating agents are mixed with the dry granules to obtain the final composition.

The compositions of the invention may be administered orally in the form of tablets, pills, or suspensions. Tablets can be prepared by methods known in technology and contain a therapeutically useful amount of the erythromycin derivative and certain excipients as needed to form the tablet by these methods. Tablets and pills can be additionally prepared using coatings

enteric coatings and other release-controlled coatings for the purpose of light protection and swallowability. The packaging may be colored using a pharmaceutically accepted dye. The amount of dye and other excipients in the coating liquid may vary and will not affect the performance of extended-release tablets. The packaging liquid usually contains film forming polymers such as hydroxy-propyl cellulose, hydroxypropylmethyl cellulose, cellulose ether or ester, acrylic polymer or a mixture of polymers. The encapsulating solution is usually an aqueous solution that also contains propylene glycol, sorbitan monooleate, sorbic acid, fillers such as titanium dioxide, and a pharmaceutically acceptable dye.

Liquid oral dosage forms may include emulsions, microemulsions, solutions, suspensions, pharmaceutically acceptable syrups and elixirs containing inert diluents commonly used in technology such as water. These formulations may also contain adjuvants, such as wetting agents; emulsifying agents and suspending agents; Sweetening agents, flavoring agents, and perfuming agents

The daily dose of the composition of this invention, which is given to the host in the form of a standardized dose, ranges from 500 mg to 1000 mg once a day for a period ranging from 5-14 days.

Pharmacokinetic study

A study of the bioavailability of the compositions of the invention can be performed by administering the extended-release composition in tablet form to healthy subjects and measuring the levels of the erythromycin derivative in plasma at various time intervals within 24 hours.

Plasma samples were assayed to determine the erythromycin derivative at BAS Analytics (West Lafayette, IN) using a high-performance liquid chromatography method. High-performance liquid chromatography was prescribed similar to that described in the leaflet. See, for example, what was reported by Chu SY, and his collaborators, in a paper entitled & Simultaneous determination of clarithromycin and 14(R)-hydroxyclarithromycin in plasma and urine using high-performance liquid chromatography with electrochemical

detection&, in J. Chromatog, vol. 571, pp. 199-208, 1991 AD. Harmful effects and side effects of taste

Adverse effects, including those related to the gastrointestinal, nervous, respiratory, and sensory systems, including taste impairment, are measured by giving subjects several doses of 1000 mg sustained-release and immediate-release tablets per day, respectively. Adverse effects are monitored, automatically recorded by subjects and recorded on case report forms to obtain a study database.

The invention will be more fully illustrated by the following examples, which are given as an example. For clarification only, which serves to provide a clearer understanding of the invention and explains its various embodiments in addition to its various advantages. Examples

Example 1

Preparing the installation

Charge Methocel™ (K 100 LV), available from Dow Chemical Company, in a mixer, and mix dryly with clarithromycin. The mixture was granulated with water until a suitable granulation was obtained. Then the granules were dried, sieved and ground to a suitable size.

Sift the talc and magnesium stearate and mix them with the dry granules. The granules are then charged into a hopper and pressed into tablets. The tablets were then coated with a water-based coating.

Three different compositions B, A, and C were prepared according to the general method described above.

Table 1 below shows three different tablet compositions.

<img file="SA920B1_D0001.tif" />

Example 2

Pharmacokinetic study of a long-term release formulation A bioavailability study was conducted to determine the concentration-time profile in plasma on healthy subjects. The study was conducted as a legally available, randomized, single-dose, single-phase, four-course, balanced-shift study, as described below. Single-dose study

24 healthy adults were enrolled and 23 completed all phases of the study. The average age of the 23 people who completed all phases of the study (12 males and 11 females) was 29 years.

(range, 19-49 years), their average weight was 69 kg (range, 51.5 to 85 kg), and their average height was 172 cm (range, 157 to 192 cm).

Clarithromycin 500 mg extended-release tablets corresponding to formulations B, A, and C shown in Example 1 and clarithromycin 500 mg immediate-release tablet (reference formulation), currently sold by Abbott Laboratories under the trade name Biaxin (brand Commercial) BIAXIN™, for 23 healthy people.

The study was conducted according to the legally available single-dose, randomized, four-course alternation method, where each subject received a single 500 mg dose of clarithromycin every 30 minutes after breakfast. Wash-out periods are separated by one-week dosing.

Blood samples of 7 ml each were collected before the dose was given (at zero hours).

And after 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours after each dose. Plasma samples were assayed for clarithromycin at BAS Analytics (West Lafayette, IN) using an established high-performance liquid chromatography method.

Pharmacokinetic analyses

Observed values for clarithromycin pharmacokinetic variables, including Tmax, Cmax, and ∞-AUC0, were calculated using standard nonparametric methods.

noncompartmental methods

Figure 1 shows the mean plasma concentration-time profiles of the single-dose study.

Figure 1 shows that all three compositions according to the invention provide a substantially equivalent long-acting release of clarithromycin within 24 hours.

Table II summarizes the pharmacokinetic results obtained after a single dose in the previous study.

<img file="SA920B1_D0002.tif" />

*Statistically significantly different from the instant-release reference disc. # It differs significantly statistically from Structures A and C in logit analysis. Statistical analyses

An analysis of variance (ANOVA) was conducted for the values of Tmax, AUC0-∞, Cmax, and the logarithms of Cmax, and ∞-AUC0, considering series, subjects within a series, course, and composition as sources of variance. Effects on subjects were random and all other effects were fixed. Within a range ANOVA, the compositions were compared pairwise, and the significance level of each test was 0.05, and the bioequivalence of the long-term release formulations with the immediate-release reference formulation was estimated. Also within the range of ANOVA for logarithm ∞-AUC0, using the two-sided test method with 90% confidence intervals. Confidence intervals were obtained by raising the final points of the confidence intervals to the strength of the difference of log means.

Table III below shows point estimates of relative bioabundance and 90% confidence intervals.

For the two-sided test method of log-transformed ∞-AUC0 analysis.

<img file="SA920B1_D0003.tif" />

Central ∞-AUC0 values were lower for each of the three long-release formulations compared to the immediate-release reference tablet. Lower Cmax and higher Tmax values suggest that all extended-release formulations containing varying weight percentages of polymer ensure long-term release of clarithromycin in vivo.

The lower ∞-AUC0 values for the extended-release formulations may suggest that the extent of absorption of clarithromycin is reduced relative to the reference immediate-release tablet when a single 500 mg dose is administered under nonfasting conditions. Multi-dose study

24 healthy adults were enrolled and 23 completed all phases of the study. The average age of the 23 people who completed all phases of the study (19 males, 4 females) was 30 years (range, 20-47 years), their average weight was 72 kg (range, 51-87 kg), and their average height was 176 cm (range, 159). to 189.5 cm).

The clarithromycin dosage forms included two 500 mg extended-release tablets in Example 1 containing 10% or 20% by weight of K100 LV, respectively, and a reference 500 mg immediate-release tablet (BIAXIN).

The study was conducted according to the legally available, three-cycle, randomized, alternating method.

Single and multiple doses. System A

A single 1000 mg dose of extended-release formulation A tablets (two 500 mg tablets) was given on the morning of day 1. From the beginning of day 3, several doses of clarithromycin 1000 mg (two 500 mg tablets) were given each morning for three days (days 3-5). System B

A single 1000 mg dose of extended-release formulation B tablets (two 500 mg tablets) was given on the morning of day 1. From the beginning of day 3, several doses of...

Clarithromycin 1,000 mg (two 500 mg tablets) every morning for three days

(Days 3-5).

System C

A single 500 mg dose of an immediate-release tablet (BIAXIN) was given in the morning of day 1. From the beginning of day 3, several doses of the reference BIAXIN 500 mg tablet were given every 12 hours for three days.

Each morning a dose was given 30 minutes after breakfast. Each evening, a dose was given 30 minutes after starting a snack.

Cleanse intervals of at least one week separated the last dose in a cycle from the last dose

The first in a subsequent cycle.

Blood samples, each amounting to 7 ml, were collected before the dose was given on day 1 (at zero hours) and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours after the dose was given. For System C, the 12 o'clock sample was collected 5 minutes before the evening dose on day 5. The resulting plasma from each blood sample was divided into two parts: one of approximately 5 ml was used for bioassay and the rest of the sample was used for high-performance liquid chromatography (HPLC). Plasma samples were assayed for clarithromycin at BAS Analytics (West Lafayette, IN) using an established high-performance liquid chromatography method. Pharmacokinetic analyses

Estimates of pharmacokinetic variables were calculated using nonparametric methods. In day 1 data, estimated variables included AUC0-∞, Tmax, Cmax or AUC0-48, and t1/2. In day 5 data, variables estimated included AUC0-24, Cmin, Tmax, Cmax, and degree of oscillation (DFL). Statistical analyses

No statistical analyzes were performed on the bioassay data. Analysis of variance (ANOVA) was conducted for the pharmacokinetic variables for day 1 and day 5 considering the effects of administration regimen

Dosage, course, series, and people included in a series. The Cmax and AUC0-∞ values for System C were adjusted to the 1000 mg dose. A logarithmic transformation was used for the AUC and Cmax values for day 1 and day 5, and the fluctuation score values for day 5 for each analysis. Both systems A and B were compared with reference system C at a significance level of 0.05. Within ANOVA of day 5 AUC values, the equivalence of the extended-release formulations in accordance with the invention to the immediate-release reference tablet was estimated using the one-sided two-test method via confidence intervals

It is 90%.

Figure 2 shows the mean plasma concentration-time profiles of the multiple-dose study.

Table IV summarizes the pharmacokinetic parameter estimates at day 5 for clarithromycin in the extended-release and immediate-release formulations as mean ± standard deviation.

<img file="SA920B1_D0004.tif" />

<img file="SA920B1_D0005.tif" />

In this multiple-dose study in unsteady conditions, both the 10% and 20% polymer extended-release formulations were bioequivalent to the tablet.

Reference immediate release for 24-AUC0. The significantly lower central Cmax and larger Tmax values suggest that both formulations provide long-term release of clarithromycin.

clarithromycin in vivo. The significantly lower degrees of fluctuation indicate that plasma concentrations fluctuate less with the two extended-release tablet systems than with the immediate-release tablet system. In addition, the significantly lower degree of fluctuation for System A compared to System B indicates that the plasma concentrations of the 20% polymer formulation fluctuate less than the tablet formulation containing 10% polymer. Adverse effects

Adverse effects, including taste impairment, of the multiple-dose regimens described above have been studied. Multi-dose study

Compositions A and B according to Example 1 (500 mg tablets) and BIAXIN 500 g (reference) immediate-release tablet were administered to healthy subjects in a multiple-dose regimen as described above. Compositions of the invention

A single dose (2 x 500 mg) of Compositions A and B according to Example 1 was given to the subjects, followed by a 48-hour clean-up period. Multiple doses were given in the morning using a 2 x 500 mg dose regimen, once a day, followed by a clean-up period for the next 3 days.

Reference composition

A single dose of BIAXIN 500 mg immediate-release tablet was given to subjects, followed by a 48-hour packing period. Several doses of the 500 mg tablet were given, twice a day followed by a three-day cleanse period.

The harmful effects on the body as a whole, and on the cardiovascular system, the digestive system, the nervous system, the respiratory system, the skin and appendages, and the special senses were measured by monitoring people at regular intervals of time. People who registered the same COSTART term more than once counted this COSTART term only once.

Table VI below shows the results for adverse effects.

<img file="SA920B1_D0006.tif" />

It is clear from Table VI above that the adverse gastrointestinal, nervous and respiratory effects commonly associated with BIAXIN are reduced with the use of long-term release tablets. Taste deterioration is significantly reduced using the compositions of the invention. And he believes

<img file="SA920B1_D0007.tif" />

It is plausible that reduced adverse effects, especially taste spoilage, will lead to a better response and a higher extent of effect to the completion of the prescribed treatment regimen. -

Table VII below shows the results of a comparative pharmacokinetic study for controlled-release formulation A.

Set forth in the applicant's pending US patent application for patent 08/574,877, filed on December 19, 1995, is a comparison with immediate-release BIAXIN.

<img file="SA920B1_D0008.tif" />

Arithmetic averages.

B standard deviation.

C is defined as the ratio of the geometric means of the test versus the regression fitting.

As shown in the table above, the values of the average degree of fluctuation for the installation are controlled

Release and immediate-release formulations are substantially equivalent, compare 1.8 ± 0.572 (for controlled-release formulation) with 1.9 ± 0.616 (for immediate-release formulation).

The average degree of fluctuation of the composition of the invention is statistically lower than the side effect of the composition immediately released in the living body. The lower degree of fluctuation indicates that the extended-release compositions of the invention provide less variable clarithromycin concentrations throughout the day compared to the immediate-release and extended-release compositions.

sustained release compositions