WO2012080984A2

WO2012080984A2 - Controlled-release pharmaceutical tablet for oral administration

Info

Publication number: WO2012080984A2
Application number: PCT/IB2011/055720
Authority: WO
Inventors: Héctor SENOSIAIN ARROYO; María Angélica ARZOLA PANIAGUA; Gustavo BARRANCO HERNÁNDEZ
Original assignee: Laboratorios Senosiain S.A. De C.V.
Priority date: 2010-12-17
Filing date: 2011-12-16
Publication date: 2012-06-21
Also published as: GT201300154A; DOP2013000136A; BR112013014963A2; PE20140675A1; WO2012080984A3; CR20130288A; RU2013127408A; MX2010014153A; RU2603469C2; CL2013001707A1; ECSP13012766A; CO6721021A2

Abstract

The invention relates to pharmaceutical compositions in the form of tablets for oral administration, containing an active principle and pharmaceutically acceptable excipients. The tablets are characterised in that one part of the active principle is released immediately, while another part of the active principle is located in a polymer diffusion matrix system that allows the active principle to be released in a delayed manner.

Description

COMPRESSED PHARMACEUTICAL CONTROLLED RELEASE FOR

ORAL ADMINISTRATION

FIELD OF THE INVENTION

The present invention relates to modified release pharmaceutical compositions in the form of tablets for oral administration, additionally also relates to the process for the preparation of said compositions.

BACKGROUND OF THE INVENTION

Of the dosage forms, the oral administration forms are the most accepted and comfortable for administration.

Some active ingredients, such as antibiotics, require strict compliance with the patient's treatment. Efforts have been made to provide modified-release formulations that are administered only once a day, seeking to generate greater comfort for treatment compliance.

In the case of quinolone-derived antibiotics, it is very difficult to develop oral administration preparations that are administered only once a day and that ensure sufficiently effective antibiotic activity. He

Ciprofloxacin is a quinolone derivative that is absorbed quickly in the gastrointestinal tract, so it is desirable to have a pharmaceutical composition that allows the antibiotic to be released in a controlled manner.

The present invention presents a formulation and a manufacturing process of a modified release drug, with a release profile that allows its administration once a day and that contains at least one active ingredient, for example an antibiotic, such as ciprofloxacin. or other quinolone derivative, as well as its pharmaceutically acceptable salts.

Ciprofloxacin is a broad-spectrum antibiotic, active against Gram-positive and Gram-negative bacteria both in the rapid development phase and in the stationary phase, acting at minimum inhibitory concentrations between 0.01 and 2 mcg / mL. It is useful for treating or preventing bacterial infections of the urinary and respiratory tract, sexually transmitted diseases, septicemia, legionellosis and atypical mycobacteriosis.

Depending on the condition, ciprofloxacin can be administered from 500 to 1,500 mg / day, divided into two doses per day for 7 to 14 days. A single dose of 250 mg is recommended in the treatment of uncomplicated gonococcal urethritis.

Different techniques are known for the preparation of modified release compositions of the active ingredient. Frequently it is intended that the composition remains a prolonged time in the stomach to allow adequate absorption In other embodiments, other sections of the gastrointestinal tract may be preferred.

U.S. Patent Nos. 5,007,790; 5,582,837 and 5,972,389 describe sustained release dosage forms for oral administration, designed to deliver a pharmacologically active agent for a prolonged period of time. In these dosage forms, the active ingredient is dispersed in a plurality of polymeric particles, which have the ability to absorb water, causing swelling. When the dosage form increases in size, it is prevented from passing through the pylorus into the lower gastrointestinal tract and therefore, the release of the drug takes place in the stomach and in the upper gastrointestinal tract.

The Mexican patent No. MX 245737 (EP1294363) of Depomed, presents an oral dosage form of controlled release comprising: a matrix containing an antibiotic, the matrix has two orthogonal axes of unequal length. After immersion in water, the matrix swells along both axes. The matrix has a shape such that when it is projected on a plane it is an oval or a parallelogram. With this system swallowing of the pharmaceutical form is facilitated and the passage through the pylorus is prevented.

As is evident from the aforementioned patents, gastric retention is determined by the degree of swelling of the pharmaceutical form in contact with the aqueous medium. However, a disadvantage of the previously described formulations is that if the pharmaceutical form is divided into two or more fragments before ingesting it, which commonly occurs when the patient finds difficulty at the moment of ingesting the complete pharmaceutical form, gastric retention It will be minimal or nil, and the release of the active ingredient will also be modified. Unlike the aforementioned formulations, the composition of the present invention does not swell during the water immersion process. The active principle release control is based on a polymeric matrix and diffusion system, independent of the tablet form.

Bayer patent MX 243623 (EP 1296685 Bl), offers an oral administration preparation containing a quinolone antibiotic, characterized in that it contains: a) water-swellable polymer and b) a mixture of at least two derivatives of the quinolone antibiotic, which they can be the free base and salt, for example, ciprofloxacin betaine and ciprofloxacin hydrochloride. The composition is a two-layer tablet containing: a quick-release part, which may contain the salt and base mixture free of ciprofloxacin, disintegrant (eg PVP) and excipients, as well as another delayed-release part that may contain the mixture of salt and ciprofloxacin free base, retardant polymer (for example, low viscosity polymer such as HPMC (hydroxypropyl methylcellulose)), organic acid (for example, succinic acid) and excipients.

A disadvantage of the composition of the MX 243623 patent, as in other inflatable formulations, is that if the pharmaceutical form is divided into two or more fragments before ingestion, the release of the active ingredient will also be modified. The composition of the present invention allows to obtain a release of active ingredient both fast and modified, and the release is not affected if the pharmaceutical form is divided before ingestion. Another disadvantage of the composition, MX 243623 patent is that both ciprofloxacin betaine and ciprofloxacin hydrochloride are used. It is well known that the basic form of ciprofloxacin is more unstable than salt, so that a stabilizing agent is required. In contrast, the composition of the present invention does not necessarily require a stabilizing agent, since more stable forms of the active ingredient, such as a ciprofloxacin salt, can be used. This allows to reduce operating times and costs.

Patent document MX / a / 2001/002634 (EP 1 107 741) of Ranbaxy, offers an oral controlled release formulation in tablets containing an effective amount of ciprofloxacin base, and approximately 0.2% to 0.5% sodium alginate , 0.5% to 2.0% xanthan gum, 25% sodium bicarbonate as a gas generating agent and 20% of polyvinylpyrrolidone. This controlled release formulation is swollen by the effect of sodium bicarbonate and sodium alginate. Upon swelling, the tablet is retained in the lower part of the stomach and before passing through the pylorus, thereby achieving a controlled release of ciprofloxacin at the site of absorption.

Patent document MX / a / 2002/008568 (EP 1263409) of Ranbaxy, offers an oral formulation of controlled release in tablets for administration once a day, which contains an effective amount of ciprofloxacin base and a viscolizing agent (also called viscous agent) ), a carboxylic or cellulose gum, gelling agent (also called gelling agent) sodium alginate, gas generating agent (carbonate or sodium bicarbonate) and a swelling agent (crosslinked polyvinyl pyrrolidone).

Unlike the formulations described in patent applications MX / a / 2001/002634 and MX / a / 2002/008568, the present invention presents a modified release formulation comprising an active ingredient, but not limited to, a derivative of Quinolone as ciprofloxacin hydrochloride, without the inclusion of gas-generating agents or gelling networks, which makes it not an inflatable formulation. Instead, there is a polymeric matrix system for diffusion of the active substance, which complies with a release profile for administration once a day. For this, excipients are used that delay the release of the active ingredient, coated by a matrix polymeric that in contact with the gastric medium is eroded to form a plurality of channels through which the active substance is released by diffusion.

There are currently several commercial presentations of oral ciprofloxacin immediate release administration 2 to 3 times a day and prolonged release with 500mg or 10mg, these formulations have an approximate absolute bioavailability of 50%.

The present invention relates to a modified release composition, which represents an advantage at the time of administration since greater adherence to the treatment regimen is achieved, the administration of the medicament being once a day for the required period. JUSTIFICATION OF THE INVENTION.

As can be seen from the state of the art, there is a wide variety of pharmaceutical compositions that offer controlled release formulations of active ingredient, however, all of them are obtained through processes made with the use of a large number of excipients. In contrast, the present invention offers a combination of systems that allow obtaining a composition that allows to achieve a controlled release profile, and that in a preferred embodiment the release is modified tangentially, using a smaller amount of excipients and using a smaller amount of inputs, time and labor during the preparation of the composition. Another innovation of the composition is the use of a barrier-diffuser matrix with a double function: taste masking and diffusion barrier. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the plasma level curves against the absorption time of the formulation of the present invention (Graph with white circuits) compared to a reference formulation (commercial product, Bayer's Cipro XR®, inflatable tablet) (Graph with black circuits).

DESCRIPTION OF THE INVENTION

The challenge faced by the development of the present invention is to obtain an oral pharmaceutical composition, which complies with the required release profile of the active ingredient and that in a preferred embodiment the release is modified tangentially, for administration once daily, where the resulting composition is stable, safe and with therapeutic efficacy.

The composition of the present invention offers a combination of systems that makes it possible to obtain modified tangential release of the active ingredient, using a smaller amount of excipients and using a smaller amount of inputs, time and labor during the preparation of the composition.

In the formulation of the present invention the use of excipients in relation to the amount of active ingredient, which allows to obtain a pharmaceutical form of easy swallowing.

With the process developed in the present invention, a polymeric matrix release system is created that doses the active ingredient in two continuous phases at two different rates in the same dose unit. This system consists of an internal part of delayed release, and an external part of rapid release. The delayed-release part contains the active substance and excipients that give it protection and allow it to delay the release of ciprofloxacin abroad. In this part, it is exposed to the active principle by a two-way controlled release: diffusion through a polymeric matrix and release through the channels formed by erosion of a polymeric matrix. The combination of these release processes results in an active principle release process in a modified and controlled manner.

The composition within the organism exhibits a release suitable for oral administration once a day by combining diffusion and erosion systems.

It is evident to one skilled in the art the complexity of obtaining compositions of easy swallowing and with modified release systems, wherein the active ingredient is included in amounts equal to or greater than 500mg. A such a high amount of active ingredient would imply the use of a large number of excipients. However, with the composition and the process of obtaining the present invention, a tablet is obtained that allows it to be more accepted by the patient who has swallowing problems, stable, safe, which allows masking the unpleasant taste of ciprofloxacin. Surprisingly, in the present invention, the active ingredient comprises about 80% by weight of the formulation and the excipients about 20%.

The components of the formulation are:

. Active ingredient: the active substance is selected from any drug that is required to be administered in a modified and / or delayed manner, this may be a quinolone derivative such as ciprofloxacin or pharmaceutically acceptable salts thereof.

• Binder diluent: it can be selected from microcrystalline cellulose, polivilpyrrolidone, hydroxypropyl methylcellulose, lactose, starch, calcium dibasic phosphate, mixture thereof or other equivalent excipient. Microcrystalline cellulose is preferred. This excipient is in the formulation in a range of 10% to 20% by weight and in a preferred embodiment is between 10% to 15% by weight.

· Retardant polymer: selected from ethyl cellulose, oleic oil, derivatives of the copolymer of methacrylic acid, cellulose acetate, methyl cellulose. This excipient is found in the formulation in a range of 0.5 to 6% by weight and in a preferred embodiment is between 3% to 6% by weight.

Matrix forming polymer: selected from HPMC (hydroxypropyl methylcellulose or hypromellose), hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose, derived from methacrylate acid copolymers. This component is in the formulation in a range of 0.5 to 10% by weight and in a preferred embodiment is between 5% to 10% by weight.

Diluent or diluent agent: can be selected from: lactose monohydrate, microcrystalline cellulose, dextrose, sucralose or sucrose and / or mannitol.

Sliding: is selected from magnesium stearate, magnesium phosphate, stearic acid, glyceryl stearate, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, talc, mixture thereof or other equivalent excipient.

Coating polymer: can be selected from cellulose and methacrylate derivatives, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl methylcellulose, carrageenan or any other equivalent excipient. FORMULATIONS:

Table 1 illustrates three examples of formulations obtained during the development of the present invention. TABLE 1

* HPMC is hydroxypropyl methylcellulose and PM means molecular weight

** Water is removed in the manufacturing process

Critical excipients in the present formulation are the "retarding polymer" and the "matrix forming polymer." HPMC "high molecular weight" polymers are recommended by manufacturers of excipients for modified release, however, it was observed that when using these high molecular weight polymers as matrix formers in With ciprofloxacin formulations, a considerable delay of the release is obtained and therefore the active principle is not released in the times to comply with the specification. On the other hand, HPMC 5 of very low molecular weight does allow the release at specified times.

In a dissolution study, the modified release formulations 1, 2 and 3 of the present invention were evaluated against the commercial formulation of patent MX243623 (reference formulation). The results are shown in Table 2. It was found that formulations 1 and 2 did not reach the required dissolution profile, but with formulation 3 the release profiles were similar to those of the reference formula.

TABLE 2

Tablet formulations in the form of coated tablets were evaluated with stability studies to verify that they are robust and compliant formulations and They retain their stability. Table 3 shows the results of a stability test for formulation 3, which shows that under different conditions it retains the characteristics of being an oblong, homogeneous and smooth tablet.

TABLE 3

Table 4 shows the general tablet formulation in the form of tablets, according to formulation 3.

TABLE 4

* It evaporates during the process A preferred formulation without limiting the scope of the present invention is that which contains from 250 mg to 1500 mg of active ingredient.

Tablet formulations in the form of coated tablets can be made without limiting the scope of the present invention in presentations containing from 250mg, 500mg, 750mg, lOOOmg and up to 1500mg of ciprofloxacin, some examples are shown in Table 5.

TABLE 5. PREFERRED GENERAL FORMULATION OF TABLETS

TABLETS

* It evaporates during the process The excipients used do not represent more than 20% of the weight of the formulation. Through a careful selection of excipients a formulation was achieved that allows using the least amount of them. This is because the matrix forming polymer and the retarding polymer have a double function. The matrix forming polymer is also a taste masking. The polymer that delays the release of the active ingredient also acts as a lubricant with good flow properties, which obviously results in a reduction in operating times and material supply costs.

A method for preparing the composition in the form of tablets is described below, without being limiting of the present invention.

1. Granulate the active substance (ciprofloxacin or a pharmaceutically acceptable salt thereof) and water (granulate 1) ·

2. Granular hypromellose, the active substance and water (granulate 2).

3. In a bowl mix ethyl cellulose and water.

4. Mix in a fluidized bed the mixture of ethyl cellulose and granulate 2.

5. In another bowl mix the granules 1 and 2 that were mixed in the previous step.

6. Apart sift and mix lactose monohydrate and microcrystalline cellulose. 7. Mix magnesium stearate with the sieve from step 6.

8. Mix the material obtained in steps 5 and 7.

9. The final mixture obtained from step 8 is compressed.

10. Optionally the obtained tablet is placed in the coater where it is sprayed with the final protective cover.

11. The finished product is conditioned. The formulations obtained do not limit the content of the active ingredients to the formulations presented as examples, since they can be presented with any other active ingredient capable of being integrated into the formulation. In the preferred embodiment, the active ingredients used are derivatives of quinolones selected from enoxacin, ofloxacin, norfloxacin, ciprofloxacin, levofloxacin, fleroxacin, perfloxacin, trovafloxacin and their pharmaceutically acceptable salts or hydrates.

By virtue of the foregoing, the present invention provides oral pharmaceutical compositions comprising an active ingredient, such as a quinolone derivative, or its pharmaceutically acceptable salts or hydrates, from 500 mg to 1000 mg even up to 1,500 mg in one same dose unit, without compromising the controlled release of the composition.

A Bioequivalence Study of the composition was carried out to know the concentration, time of release of the active substance ciprofloxacin or its acceptable pharmaceutical salts, in its healthy etho-volunteers. A cross-sectional study was carried out two sequences, two periods (2x2) at a therapeutic dose of 1 g of ciprofloxacin contained in a dose unit (tablet).

The study involved 26 healthy volunteers who received orally lg of ciprofloxacin, 17 samples were obtained from each individual over a 24-hour period.

Plasma samples were processed through the liquid-liquid extraction technique and ciprofloxacin concentrations were determined by the High Resolution Liquid Chromatography Method.

Figure 1 shows the plasma level curves of the formulation of the present invention (white circles) and a reference formulation (black circles). This figure shows that the formulation of the present invention meets the required characteristics such as a release greater than 40% in the first hour and greater than 80% after 4 hours.

From the graphs in Figure 1, the pharmacokinetic parameters, Maximum Concentration (Cmax), area under the curve at the last sampling point (ABC 0-t) and area under the curve extrapolating to infinity (ABC 0-00) were obtained ). The arithmetic scale averages of the study periods of ciprofloxacin plasma concentration in healthy volunteers are shown in Table 6. In this table, A is the reference product and B is the tablet composition of the present invention.

The graphic analysis suggests that the ciprofloxacin i.armacokinetic profiles in both products overlap.

TABLE 6

With the results shown in Table 6, it can be concluded that the composition of the present invention, once-daily extended-release tablet, is bioequivalent with the reference formulation, but the advantage that only one ciprofloxacin derivative is used and that the release of the active substance is independent of the swelling of the pharmaceutical form.

Another advantage seen from the composition of the present invention is that it is effective and safe in its administration.

The invention has been described sufficiently that a person with average knowledge in the field can reproduce and obtain the results mentioned in this description. However, any skilled person in the field of the art that is in charge of the present invention may be able to make modifications not described in the present application. However, if the subject matter claimed in the following claims is required for the application of these modifications in a given composition, said compositions should be within the scope of the present invention.

Claims

1. A controlled-release tablet for oral administration, characterized in that the active ingredient is in a polymeric matrix and diffusion system formed by a retarding polymer and a matrix-forming polymer.

2. The controlled-release tablet for oral administration according to claim 1, wherein the active ingredient is a quinolone derivative.

3. The controlled-release tablet for oral administration according to claim 2, wherein the derivative is selected from enoxacin, ofloxacin, norfloxacin, ciprofloxacin base, ciprofloxacin hydrochloride, levofloxacin, fleroxacin, perfloxacin, trovafloxacin and pharmaceutically stable salts or hydrates.

4. The controlled-release tablet for oral administration according to claim 3, wherein the quinolone derivative is ciprofloxacin hydrochloride or its pharmaceutically stable salts or hydrates.

5. The controlled-release tablet for oral administration according to claim 1, characterized in that the active ingredient is in an amount of 250 mg to 1500 mg per dose unit.

6. The controlled-release tablet for oral administration according to claim 1, which additionally includes at least the following excipients: diluent binder, diluent, slider and, optionally, a coating polymer.

7. The controlled release tablet for oral administration according to claim 6, wherein the content of the excipients is: 10% to 20% binder diluent, 0.5% to 6% retardant polymer, 0.5% to 10 matrix forming polymer %, diluent from 1% to 20%, sliding from 0.5% to 2% and coating polymer from 1.5% to 3%.

8. The controlled-release tablet for oral administration according to claim 1 characterized in that the retarding polymer and the matrix-forming polymer can be derived from cellulose or methacrylic acid.

9. The controlled release tablet for oral administration according to claim 8, wherein the retarding polymer is selected from ethyl cellulose, oleic oil, derivatives of the copolymer of methacrylic acid, cellulose acetate, methyl cellulose, preferably ethyl cellulose.

10. The controlled-release tablet for oral administration according to claim 8, wherein the matrix-forming polymer is selected from hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose, derived from methacrylate acid copolymers.

11. The controlled-release tablet for oral administration according to claim 10, wherein the Matrix forming polymer is low molecular weight hydroxypropyl methylcellulose.

12. The controlled-release tablet for oral administration according to claim 1, wherein the tablet is an oblong, homogeneous and smooth tablet.

13. A method for preparing pharmaceutical composition containing a quinolone derivative, characterized in that in one stage a part of the active ingredient and water (granulate 1) is granulated; in another stage the rest of the active ingredient is granulated with matrix forming polymer, retarding polymer and water (granulate 2); subsequently both granules are combined with a diluent binder, diluent and slider; the material obtained from the previous stage is compressed and optionally a final protective cover is added.

14. The use of the pharmaceutical tablet of claims 1 to 12, to prepare an oral administration medicament.