Pharmaceutical composition comprising an antimicrobial agent and method for the preparation thereof

Abstract

The present invention relates to a stable pharmaceutical formulation of solid dosage forms for oral administration comprising an antimicrobial agent such as Rifaximin or a pharmaceutical acceptable salt, derivative or polymorph thereof as the active ingredient. It also relates to an innovative process for the preparation thereof.

Description

[0001] PHARMACEUTICAL COMPOSITION COMPRISING AN ANTIMICROBIAL AGENT AND METHOD FOR THE PREPARATION THEREOF

[0002] TECHNICAL FIELD OF THE INVENTION

[0003] The present invention relates to a stable pharmaceutical formulation for oral administration containing a therapeutically effective quantity of an antimicrobial agent such as Rifaximin or pharmaceutical acceptable salt, derivative or polymorph thereof and a method for the preparation thereof.

[0004] BACKGROUND OF THE INVENTION

[0005] Antibiotics are used to treat bacterial infections. They are classified in various categories depending on their antimicrobial spectra, pharmacodynamics and chemical composition.

[0006] Rifaximin is a rifamycin-based non-systemic antibiotic used for the treatment of gastrointestinal bacterial infections, such as traveller’s diarrhea and irritable bowel syndrome, and reduction of overt hepatic encephalopathy recurrence in adults. As the other rifamycins, it is a poorly absorbed bactericidal rifamycin derivative and exerts its antibacterial activity by binding to RpoB, the B-subunit of bacterial DNA-dependent RNA polymerase, thus inhibiting bacterial RNA synthesis. Animal and human studies demonstrate that the systemic absorption of Rifaximin into the bloodstream, after oral administration, is negligible, being less than 0.4% of the administered dose.

[0007] The discovery of polymorphism of Rifaximin in the early 2000s showed that the bioavailability of Rifaximin is strictly correlated to its polymorphic form, being the alpha form one of the less bioavailable. Rifaximin is a topical antibiotic, and, in fact, it exerts its antibacterial activity against microorganisms that cause gastrointestinal infections, but not systemic infections. Indeed, Rifaximin, released in the gastrointestinal tract, is excreted, primarily, in feces as unchanged drug. Because of its localized activity, Rifaximin has a favourable side-effect profile and a low potential for drug interactions.

[0008] Rifaximin exhibits a broad spectrum of in vitro and in vivo activity, modulates microbial virulence and epithelial cell function. The variety of the Rifaximin actions, in addition to its antimicrobial effects, may potentially explain the effects of the drug in variety of diseases and syndromes. In fact, although it has been shown to have both bactericidal and bacteriostatic properties that account for some of the antimicrobial effects observed in Rifaximin treatment, one of the most intriguing aspects of this drug is that it can shorten the duration of infection, without eradicating enteropathogens and with minimal effects on the colonic bacterial flora. In fact, the most peculiar characteristic of Rifaximin, with respect to other antibiotics, is its efficacy without significant changes in gut microbiota composition.

[0009] The chemical name of Rifaximin is 2S,16Z,18E,20S,21S,22R,23R,24R,25S,26R,27S,28E)- 5,6,21,23-Tetrahydroxy-27-methoxy-2, 4, 11, 16, 20, 22, 24, 26 -octamethyl- 1, 15-dioxo-l, 2- dihydro -2, 7- (epoxypentadecal [1, 11, 13] - trienoimino) [1] benzofuro [4, 5 - e] pyrido [1, 2- a]benzimidazol-25-yl acetate The molecular formula is C43H51N3O11 corresponding to a molecular weight of 785.9. Rifaximin is soluble in acetone and methanol and practically insoluble in water while it is freely soluble in ethanol. It is red to orange, hygroscopic, crystalline powder and it has a high partition coefficient.

[0010] Multiple polymorphs of Rifaximin, such as alpha, beta, delta, epsilon and amorphous are reported in the literature, for example in Viscomi G et al., Crystal forms of Rifaximin and their effect on pharmaceutical properties, Crystal Eng. Comm., 2008, 10, 1074-1081 and Journal of AOAC International Vol. 99, No. 4, 2016 964.

[0011] EP-B-2059232 discloses the use of one or more compounds bearing at least two hydroxy groups dissolved in an aqueous solution to stabilize polymorphous forms of Rifaximin.

[0012] US-B-10137114 discloses a stable, taste-masked, ready-to-use suspension of Rifaximin.

[0013] Although each of the patents above represents an attempt to overcome solubility and stability issues associated with Rifaximin compositions, there still remains the need in the art for a stable pharmaceutical composition which avoids the problems related to the intrinsic nature of Rifaximin. SUMMARY OF THE INVENTION

[0014] It is an object of the present invention to provide a stable solid pharmaceutical composition for oral administration containing an antimicrobial agent and in particular Rifaximin or pharmaceutical acceptable salt, derivative or polymorph thereof as an active ingredient, which overcomes the deficiencies of the prior art.

[0015] It is, therefore, an object of the present invention to provide an oral solid dosage formulation comprising Rifaximin, which overcomes the tendency of Rifaximin to exhibit polymorphic transformation resulting in longer shelf-life of the product.

[0016] A further approach of the present invention is to provide a tablet composition for oral administration comprising Rifaximin which is manufactured through a fast, simple and cost- effective process.

[0017] A major object of the present invention is to provide an immediate release dosage form for oral administration containing Rifaximin that overcomes the low water solubility of the active ingredient and has acceptable pharmacotechnical properties.

[0018] It is another object of the present invention to provide an oral solid dosage formulation comprising Rifaximin as an active ingredient, which is bioavailable and with sufficient self-life.

[0019] In accordance with the above aspects of the present invention, a pharmaceutical composition for oral administration is provided comprising a portion of Rifaximin compound in a solid dispersion form and the remaining amount of the active ingredient in a non-dispersed, crystalline form in order to enhance the active ingredient’s solubility and gastrointestinal availability.

[0020] According to another embodiment of the present invention, a process for the preparation of a stable, solid dosage form for oral administration, containing an antibacterial agent such as Rifaximin is provided, which comprises the following steps: a) Dissolving 30% to about 80% of API stated amount in appropriate amount of organic solvent (ethanol). b) Evaporating at 35C till residual solvent level is below acceptance limit. c) Sizing of resulted API granules. d) Dry Mixing of API granules of previous step with diluent, glidant and disintegrant. e) Mixing the obtained granules with the rest of API stated amount. f) Adding lubricant and glidant and blending to prepare a homogeneous granular blend; g) Compressing the blend prepared at step (f) at specific dimensions for each product strength. h) Optionally coating the compressed tablets with appropriate coloring agent.

[0021] Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.

[0022] DETAILED DESCRIPTION OF THE INVENTION

[0023] For the purposes of the present invention, a pharmaceutical composition comprising an active ingredient (e.g. Rifaximin) is considered to be “stable” if said ingredient degrades less or more slowly than it does on its own and / or in known pharmaceutical compositions.

[0024] As already mentioned, the main object of the present invention is to provide an immediate release composition of Rifaximin or pharmaceutical acceptable salt, derivative or polymorph thereof that is simple to manufacture, bioavailable, cost effective, stable and possesses good pharmacothechnical properties.

[0025] Tablets are the most widely used solid dosage form of medicament. Because of their advantages their popularity is continuously increasing day by day. They are an excellent dosage form choice for drugs on long-term storage. The drug can be mixed with excipients that will enhance dissolution and when the tablet is ingested, rapidly disintegrates to give a drug dispersion of high surface area and good bioavailability. Tablets are easy to use, handle and carry by the patient. The manufacturing cost of tablets is low as compared to other dosage forms. The unpleasant taste and odour of medicaments can be easily masked. Different colours and markings can be added easily to the tablet, generally aiding in identification processes for the patient or health care professionals. Finally, patient acceptability of tablets is generally high, and the process of swallowing is much easier in comparison to other dosage forms. Rifaximin is a BCS Class IV drug which exhibits poor water solubility and poor permeability. One of the major challenges with the design of the current dosage form lies with Rifaximin’s poor aqueous solubility which is linked to molecule’s bioavailability. As per Savjani et al. 2012 (Drug Solubility: Importance and Enhancement Techniques), solubility is one of the important parameters to achieve desired concentration of drug in systemic circulation for achieving required pharmacological response. Poorly water-soluble drugs often require high doses in order to reach therapeutic plasma concentrations after oral administration. Any drug to be absorbed must be present in the form of an aqueous solution at the site of absorption. Most of the drugs are either weakly acidic or weakly basic having poor aqueous solubility.

[0026] It has been surprisingly found that Rifaximin’s poor solubility is significantly enhanced when a specified sequence of manufacturing steps is applied in the production of Rifaximin tablets. More specifically, a portion of the API from 30% w / w / to 80% w / w of the total API amount, is pre-dissolved in organic solvent such as ethanol and then the solvent is evaporated till residual solvent level is below acceptance limit. Then the solids of internal phase are dry mixed with the obtained API granules. The remaining excipients of product formula and portion of Rifaximin amount in crystalline form are dispensed externally in product formula. Both portions of Rifaximin compound equals to 100% of the pharmaceutically acceptable amount.

[0027] Rifaximin exhibits polymorphism and the main polymorphic forms that are known in the literature are alpha, beta, delta, epsilon and amorphous. X-Ray diffraction (XRD) data indicate that Rifaximin in compositions of the present invention matches to the alpha polymorph with characteristics peaks at 6.6, 7.4, 7.9, 8.8, 10.5, 11.1, 12.9, 17.6, 18.5, 19.7 ± 0.2° 2Theta.

[0028] The pharmaceutical compositions of the present invention may contain one or more formulation excipients such as diluents, disintegrants, binders, lubricants, glidants, colorants and flavouring agents, provided that they are compatible with the active ingredient of the composition, so that they do not interfere with it in the composition and in order to increase the stability of the drug and the self-life of the pharmaceutical product.

[0029] Diluents may be added to the formulations of the present invention. Diluents increase the bulk of a solid pharmaceutical composition and may make a pharmaceutical dosage form easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose, dextrates, dextrose, fructose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, xylitol, maltose, maltodextrin, maltitol, lactose. Preferred diluent is microcrystalline cellulose in amount of 1% to 35% by weight of the total weight of the composition.

[0030] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose function include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include alginic acid, carbomer, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, methylcellulose, polydextrose, polyethylene oxide, polyvinylpyrroline.

[0031] The dissolution rate of a compacted solid pharmaceutical composition in the patient’s stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include sodium starch glycolate, alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmelose sodium, guar gum, methylcellulose, polacrilin potassium, sodium alginate, crospovidone. Preferred disintegrant is sodium starch glycolate in amount of 1% to 5% by weight of the total weight of the composition.

[0032] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, calcium silicate, calcium phosphate tribasic, talc. Preferred glidants are talc and colloidal silicon dioxide in amount of 0.1% to 1% by weight of the total weight of the composition

[0033] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause surface irregularities to the product. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glycerol palmitostearate, glycerylbehenate, hydrogenated castor oil, stearic acid, sodium lauryl sulfate. Preferred lubricant is glycerol palmitostearate in a mount of 5% to 10% by weight of the total weight of the composition Solid compositions may optionally be dyed using any pharmaceutically acceptable colorant to improve their appearance and / or facilitate patient identification of the product and unit dosage level.

[0034] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers are, for example, mint powder, menthol, cherry flavour, xylitol, vanillin, aspartame, acesulfame potassium, saccharin.

[0035] Finally, tablets of the present invention are optionally coated with a film composition that has no effect on the release of the active ingredient from the dosage form. The film-coating composition may comprise polymers, plasticizers, surfactants, opacifiers and / or pigments, more specifically it may comprise hypromellose, titanium dioxide, disodium edetate, propylene glycol, red iron oxide, polyvinyl alcohol, talc, polyethylene glycol.

[0036] The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention.

[0037] EXAMPLES

[0038] The scope of the present invention is the preparation of an oral solid dosage form, in particular a film-coated tablet, comprising Rifaximin and exhibiting an immediate drug release profile at aqueous medium.

[0039] Example 1 :

[0040] The following qualitative formula was considered for trials. Both colloidal silicon dioxide and talc were used as glidants in current formula whereas microcrystalline cellulose was the diluent. The level provided for each excipient is below the level listed in the Inactive Ingredient Database (IID) for FDA-approved oral solid dosage forms. Linear formula is applied among the finished product strengths. Table 1 : Composition 1

[0041] Rifaximin immediate release tablets of Example 1 were prepared according to the following manufacturing process: a) Passing of excipients (microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate) and Rifaximin API through a sieve of 50 mesh and dry mixing till a homogeneous powdered mass is prepared b) Passing lubricant and glidants (talc and glycerol palmitostearate) through a 50 mesh sieve and blending to form an homogeneous powdered mass c) Compression of powder mass at appropriate punch per product strength d) Optionally coating of compressed tablets with appropriate coloring agent at a target weight gain of 2% wt.

[0042] The in vitro solubility results as well as physicochemical results of Composition 1 are stated below in Table 2.

[0043] Table 2: Physicochemical & solubility results of Composition 1 As per solubility results, it seems that a suppressed solubility rate is recorded for Composition 1. Thus, the formulation development focused on product formula optimization and solubility rate will be closely monitored through appropriate time specification (Tsomin).

[0044] A range of alternative formulation trials were prepared applying alternative levels of inactive ingredients. More specifically, the critical components that impact finished product in vitro performance were recognized through the following series of experiments.

[0045] Primarily, the disintegrant and diluent levels were evaluated via Design of Experiment (DoE) series. A 22full factorial DoE was performed to evaluate the impact of amount of microcrystalline cellulose (MCC) and sodium starch glycolate (Primojel) dispensed in the product formula.

[0046] The following quantity levels were investigated herein for Rifaximin 200 mg fc tabs product. Amount of MCC: HIGH level (200.0 mg / tab), MEDIUM level (115.0 mg / tab), LOW level (50.0 mg / tab),

[0047] Amount of Primojel: HIGH level (30.0 mg / tab), MEDIUM level (15.0 mg / tab), LOW level (5.0 mg / tab)

[0048] The responses studied were the following: drug dissolved at 30 min (Yl), disintegration (Y2), hardness (Y3) and assay (Y4).

[0049] Based on the results of Analysis of Variance (ANOVA) the following observations were made. The % drug dissolved amount at 30min, was not affect significantly by any change. The disintegration was affected by the MCC amount, the Primojel amount and their interaction. As per trials results, higher disintegration results were recorded at higher diluent levels whereas disintegration time was minimized at higher Primojel content levels for any microcrystalline cellulose amount. The results for assay showed that assay was well-within the acceptance limits for all formulation trials and no significant changes were recorded. Finally, the results for hardness, were affected by the MCC amount, the Primojel amount and their interaction. Higher hardness values are recorded at high microcrystalline cellulose levels for any Primojel amount indicating the significant impact of diluent on finished product hardness attribute. It was evident that Primojel impacts at a lower extent the hardness of tablets. Overall, considering the results recorded along current Design of Experiments (DoE), no significant impact on in-vitro solubility rate of Rifaximin and assay of finished product coated tablets was recorded for any factor. Both diluent and disintegrant at middle level (MCC: NMT 115.0 mg / tab & Primojel: NMT 15.0 mg / tab) were chosen.

[0050] Similarly, different levels of glidants were also evaluated to figure out the performance of finished product. Alternative compositions were prepared as per following series of experiments. A 22full factorial DoE was performed to evaluate the impact of amount of aerosil and talc dispensed in product formula.

[0051] The following charging quantity levels were investigated herein:

[0052] Amount of Aerosil: HIGH level (1.0 mg / tab), MEDIUM level (3.0 mg / tab), LOW level (5.0 mg / tab),

[0053] Amount of Talc: HIGH level (1.0 mg / tab), MEDIUM level (3.0 mg / tab), LOW level (5.0 mg / tab).

[0054] The responses studied were the following: drug dissolved at 30 min (Yi), blend uniformity %RSD (Y2) and flow properties of blend (Y3).

[0055] Based on the ANOVA results for % drug dissolved amount at 30min, none of the factors affect significantly the drug dissolved at 30 min. The results for Release Blend Uniformity (%RSD) the significant factors affecting the blend uniformity were the aerosil amount, the talc amount and their interaction. Considering the results, blend uniformity %RSD within acceptance criteria was recorded for all formulation trials. However, higher %RSD results were recorded at higher aerosil / lower talc amount trials. Finally, it was observed that none of the factors significantly affects the flow properties of powdered blend considering also that both aerosil and talc are present in low amount in finished product formula. Thus, the risk of impact on flowability of finished product blend is considered low.

[0056] Overall, considering that a homogeneous powdered mass was prepared for all formulation trials and none of the factors impacts the solubility rate of Rifaximin & flow properties of finished product blend, the minimum levels for both factors are considered adequate to ensure uniformity of powdered blend (Aerosil: NMT l.Omg / tab & Talc: NMT l.Omg / tab). At last, the current formulation optimization focused on glycerol palmitostearate amount. Thus, different levels of lubricant were also evaluated within the context of the current invention. Three alternative amount levels were investigated:

[0057] Low level- 5.0 mg / tab

[0058] Medium level- 18.0 mg / tab

[0059] High level- 30.0 mg / tab

[0060] Assay, % drug dissolved at 30 min and blend uniformity (%RSD) were evaluated again. Based on formulation trials results, glycerol palmitostearate content does not impact either the drug solubility rate or assay of finished product. Considering the current results, the medium level of glycerol palmitostearate was chosen for the current formulation (Glycerol palmitostearate: NLT 18.0mg / tab).

[0061] Composition 1 (Table 1) was then tested for its in vivo behavior but that was found inadequate due to poor water solubility of Rifaximin compound.

[0062] An alternative process for manufacturing the composition 1 was subsequently attempted. More specifically, the API was pre-dissolved in ethanol and then the solvent was evaporated till residual solvent level is below acceptance limit. Then the solids of the internal phase were dry mixed with the obtained API granules. The rest excipient of product formula (talc, glyceryl palmitostearate) are dispensed externally in product formula. The alternative manufacturing process of Composition 1 applied is presented below: a) Dissolution of whole amount of API in appropriate amount of ethanol. Proceed on solvent evaporation at 35C till residual solvent level is below acceptance limit. b) Sizing of API granules resulted from step 1 through 0,300mm sieve c) Dry Mixing of API resulted from step b, Microcrystalline cellulose, Colloidal silicon dioxide and Sodium starch glycolate. d) Adding Talc and Glyceryl palmitostearate and blending to prepare a homogeneous granular blend; e) Compression of blend prepared at step (f) at specific dimensions for each product strength; f) Optionally coating of compressed tablets with appropriate coloring agent. The physicochemical property results as well as solubility rate of Rifaximin of Composition 1 prepared with the alternative method were significantly improved. The composition was tested again in vivo but still the results were inadequate.

[0063] Example 2:

[0064] A different manufacturing approach was subsequently followed for pharmaceutical preparations in order to achieve the appropriate drug bioavailability.

[0065] Composition 2A, 2B and 2C were prepared as per table 3 below.

[0066] Table 3: Qualitative / Quantitative Formula of Compositions 2A to 2C The manufacturing process applied for the preparation of above-mentioned pharmaceutical Compositions 2A-2C is the following: a) Dissolution of a portion of API in appropriate amount of ethanol. Proceed on solvent evaporation at 35C till residual solvent level is below acceptance limit. b) Sizing of API granules resulted from step (a) through 0,300mm sieve c) Dry Mixing of API resulted from step (b), Microcrystalline cellulose, Colloidal silicon dioxide and Sodium starch glycolate d) Mixing the remaining portion of the total amount of Rifaximin compound with the granular mass of step (c); e) Adding Talc and Glyceryl palmitostearate and blending to prepare a homogeneous granular blend; f) Compressing the blend prepared at step (e) at specific dimensions for each product strength; g) Optionally coating of compressed tablets with appropriate coloring agent.

[0067] The assay, related substances and solubility rate of Rifaximin were recorded for the composition of table 3. Also the compositions were loaded into stability chambers and monitored with a fit- for-purpose HPLC analytical method. Stability data upon storage at zero time and 6 months under long-term (25 °C±2 °C / 60%±5% RH) and accelerated storage conditions (40 °C±2 °C / 75%±5% RH.

[0068] Based on the stability results, it can be stated that all the pharmaceutical preparation of the present invention were stable since no significant shift of solubility rate was recorded even under accelerated storage conditions for 6 months. Also, the assay and related substances after 6 months of stability at long-term and accelerated storage conditions are well within the acceptance criteria. Composition 2A presented better in vivo results nevertheless all were within the acceptance limits.

[0069] While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the spirit and scope thereof, as defined in the appended claims.

Claims

CLAIMS1. A pharmaceutical composition in the form of an orally administrable tablet comprising a) a portion from 30% to 80% w / w of the total amount of Rifaximin incorporated in the internal phase of the tablet and b) the remaining portion of Rifaximin in the external phase.

2. The pharmaceutical composition according to claim 1 further comprising: a) 1% to 5% by weight of the total weight of the composition of disintegrant, b) 5% to 10% by weight of the total weight of the composition of lubricant, c) 1% to 35% by weight of the total weight of the composition of diluent, d) 0.1% to 1% by weight of the total weight of the composition of glidant.

3. The pharmaceutical composition according to claim 2, wherein said disintegrant is sodium starch glycolate type A.

4. The pharmaceutical composition according to claim 2, wherein said glidant is colloidal silicon dioxide and / or talc.

5. The pharmaceutical composition according to claim 2, wherein said lubricant is glycerol palmitostearate.

6. The pharmaceutical composition according to claim 2, wherein said diluent is microcrystalline cellulose.

7. A process for the preparation of a pharmaceutical composition for oral administration in the form of an orally administrable tablet comprising a Rifaximin compound as the drug substance, which process comprises the following steps: a) Dissolving a portion of Rifaximin from 30% to 80% w / w of the total amount of Rifaximin in ethanol. b) Proceeding with solvent evaporation at about 35°C till residual solvent level is below acceptance limit. c) Sizing of API granules resulted from previous step through 0,300mm sieve.d) Dry mixing of API resulted from step (b), Microcrystalline cellulose, Colloidal silicon dioxide and Sodium starch glycolate e) Mixing the remaining portion of the total amount of Rifaximin compound with the granular mass of previous step. f) Adding Talc and Glyceryl palmitostearate and blending to prepare a homogeneous granular blend. g) Compression of blend prepared at step (f) at specific dimensions for each product strength. h) Optionally film coating of compressed tablets.

8. The Rifaximin compound of any of the preceding claims which is in crystalline form a.

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