WO2009018834A1

WO2009018834A1 - Pharmaceutical composition containing bisphosphonate and method for the preparation thereof

Info

Publication number: WO2009018834A1
Application number: PCT/EP2007/006923
Authority: WO
Inventors: Evangelos Karavas; Efthimios Koutris; Stavros Politis; Vicky Samara; Dimitrios Bikiaris
Original assignee: Pharmathen S.A.
Priority date: 2007-08-06
Filing date: 2007-08-06
Publication date: 2009-02-12

Abstract

The present invention relates to improved pharmaceutical formulation for oral administration comprising a therapeutically effective quantity of a bisphosphonate, and more particularly Alendronate, Risedronate or Ibandronate or salts or derivative thereof in combination with at least one polymer containing hydroxyl, carboxyl or sulphite groups or mixtures thereof to enhance bioavailability and a method for the preparation thereof.

Description

PHARMACEUTICAL COMPOSITION CONTAINING BISPHOSPHONATE AND METHOD FOR THE PREPARATION THEREOF

TECHNICAL FIELD OF THE INVENTION

The present invention relates to improved pharmaceutical formulation and in particular to a formulation for oral administration with enhanced bioavailability comprising a therapeutically effective quantity of a bisphosphonate active compound, and more particularly Alendronate, Risedronate, or Ibandronate or salts or derivatives thereof and a method for the preparation thereof. BACKGROUND OF THE INVENTION

Polyphosphonic acids and their pharmaceutically acceptable salts and derivatives have been proposed for use in the treatment and prophylaxis of a number of pathological conditions which can affect humans or other mammals and involve calcium and phosphate metabolism, like: a) Conditions which are characterized by anomalous mobilization of calcium and phosphate leading to general or specific bone loss or excessively high calcium and phosphate levels in the fluids of the body. b) Conditions which cause or result from deposition of calcium and phosphate anomalously in the body.

The first category includes osteoporosis and Paget' s disease. Osteoporosis is a condition in which bone hard tissue is lost disproportionately to the development of new hard tissue. Marrow and bone spaces become larger, fibrous binding decreases and compact bone becomes fragile. In Paget's disease, dissolution of normal bone occurs which is then haphazardly replaced by soft, poorly mineralized tissue such that the bone becomes deformed from pressures of weight bearing, particularly in the tibia and femur. Hyperparathyroidism, hypercalcemia of malignancy, and osteolytic bone metastases are conditions also included in the first category.

The second category involves conditions manifested by anomalous calcium and phosphate deposition and includes myositis ossificans progressive, calcinosis universalis, and such afflictions as arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions which predispose involved tissue to deposition of calcium phosphates.

The primary treatment option regarding all these conditions is the administration of bisphosphonates. Paget's disease and heterotopic ossification are currently successfully treated with bisphosphonates. The bisphosphonates tend to inhibit the resorption of bone tissue, which is beneficial to patients suffering from excessive bone loss.

However, bisphosphonates have many disadvantages related to the fact that they are poorly absorbed from the gastrointestinal tract. Their poor bioavailability is further reduced by the presence of food and beverages other than water. To facilitate adequate absorption from the gastrointestinal tract, it is generally recommended that oral bisphosphonates, such as alendronate and risedronate, be taken in the fasting state, 30 minutes before the first food, beverage, or medication of the day. Many patients find the need for such fasting on a daily basis to be inconvenient. Moreover, oral administration of bisphosphonate has been associated with adverse gastrointestinal effects, especially those relating to the esophagus. The adverse gastrointestinal effects always easily cause esophageal irritation.

The oral bioavailability of bisphosonates is extremely poor lying between 1% and 10% or even lower. For instance, alendronate and risedronate are the widely used, orally administrated agents for prevention and treatment of osteoporosis. Their oral bioavailability is merely 0.5%- 1% and 0.63%. The absorption would be further deducted if the bisphosphonates were given with meals, milk, coffee, orange juice, calcium, or other multivalent inorganic cations (e.g. Magnesium), due to the formation of insoluble complexes.

The small intestine of humans is the longest of the digestive tract and its effective surface area for absorption is large. Therefore, it is the ideal site for absorption of many drugs. However, epithelial cells, which have a plasma membrane made from a lipid double layer, cover the surface of the digestive tract mucous membrane site very closely and therefore absorption is strongly restricted in the case of drugs that are very water soluble and polymer drugs. Moreover, in addition to the digestive tract mucous membrane, the mucous layer that ordinarily covers the digestive tract mucous membrane also becomes a barrier blocking the absorption of drugs by the digestive tract. Consequently, drugs that have been orally administered are first absorbed in vivo after passing through the above-mentioned two barriers of the mucous layer covering the mucous membrane surface and the mucous membrane. The above-mentioned mucous layer is mainly made from the components of, glycoprotein such as mucin, cholesterol, lipids such as linoleic acid, proteins, DNA, and others, including various metal ions, such as calcium ions, etc. Moreover, the mucous membrane also contains traces of metal ions, etc. Consequently, drugs that are difficult to absorb through the digestive tract because of interaction with various biologically-derived components are present in the mucous layer and/or mucous membrane of the digestive tract.

For instance, bisphosphonate compounds have (P-C-P) bonds in their molecular structure and therefore, as with phosphonate compounds in general, have strong affinity with bivalent metal ions, such as calcium ions, etc., and bond with these metal ions to form insoluble complexes. Consequently, when bisphosphonate compounds are taken after eating or simultaneously with calcium agent, a slightly soluble complex is formed in the digestive tract and therefore, absorptivity of the bisphosphonate compound in the digestive tract is markedly reduced.

Consequently, there is a need for more efficacious treatments of bisphosphonates. Intravenous administration has been used to overcome the bioavailability problem. However, intravenous administration is costly and inconvenient, especially when the patient must be given an intravenous infusion lasting several hours on repeated occasions. Also, delayed release dosage forms have been developed in order to release the active ingredients after passage through the upper gastrointestinal tract and in some cases through the stomach, i.e., enteric coated tablets. But, in certain instances it is undesirable or unnecessary for a medicament to be in a delayed release dosage form.

Various methods are already known for the industrial preparation of oral dosage forms comprising a bisphosphonate e.g. Alendronate or Risedronate or Ibandronate or salts or derivatives thereof, as an active ingredient due to its useful therapeutical properties. However, the prior art has encountered substantial difficulties in the production of the oral solid formulations of a desirable bioavailability. It is obvious that there is a need for pharmaceutical formulations, preferably for oral administration, which are capable of enhancing the bioavailability of bisphosphonates, such as alendronate, risedronate and ibandronate, so that the patients are able to take the medication in a more convenient manner, e.g. with less quantity or in a reduced frequency or together with food intake, with calcium or with hard water. Only a few methods have been studied for enhancing the oral bioavailability, including co-administration of EDTA (which chelates calcium, consequently increases the absorption of bisphosphonate), increasing in the intraluminal pH (such as H2 receptor antagonist therapy), and using medium chain glycerides as absorption enhancer.

US 2006/0112206 discloses a pharmaceutical composition which comprises aminoalkyl methacrylate copolymer E for oral use with improved absorption by increasing drug permeability of the digestive tract mucous membrane and/or mucous layer distributed over the mucous membrane

Although each of the above patents represents an attempt to overcome the bioavailablity problems associated with pharmaceuticals compositions comprising a bisphosphonate compound or pharmaceutical acceptable salts thereof, there still exists a need for improving the bioavailability of such pharmaceutical compositions without producing unwanted pharmaceutical effects and for facilitating rapid esophageal transit, minimizing or avoiding the release of the active compound in the upper gastrointestinal tract and delivering the active ingredient to the stomach, minimizing the gastrointestinal irritation and the adverse effects. SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention to provide an improved solid dosage formulation containing a biphosphonate compound, and in particular Alendronate, Risedronate or Ibandronate or pharmaceutical acceptable salts or derivatives thereof as an active ingredient, which overcomes the deficiencies of the prior art and enhances the bioavailability of the active substance.

Another aspect of the present invention is to provide a solid dosage composition for oral administration containing a bisphosphonate, and in particular Alendronate, Risedronate or Ibandronate or pharmaceutical acceptable salts or derivatives thereof, as an active ingredient, which is bioavailable and effective with sufficient self-life, good pharmacotechnical properties enhancing patient compliance and reducing possible side effects.

Moreover, another aspect of the present invention is to provide a solid dosage formulation for oral administration containing a bisphosphonate, and in particular Alendronate, Risedronate or Ibandronate or pharmaceutical acceptable salts or derivatives thereof, as an active ingredient, which can be prepared in dosage forms of different strength by proportionally adjusting the quantities of the excipients and the active ingredient, thereby providing a pharmacotechnical linearity, without affecting the dissolution profile and bioavailability of the active ingredient.

A further aspect of the present invention is to provide a method for the preparation of a stable solid dosage formulation for oral administration containing a bisphosphonate, and in particular Alendronate, Risedronate or Ibandronate or pharmaceutical acceptable salts or derivatives thereof, as an active ingredient, thereby enhancing the bioavailability of the active ingredient, being stable over a long period of time and improving the pharmacotechnical characteristics of the composition. In accordance with the above objects of the present invention, a pharmaceutical composition for oral administration is provided comprising a pharmaceutical composition for oral administration comprising a bisphosphonate, and in particular Risedronate or Alendronate or Ibandronate or a pharmaceutical acceptable salt or derivative thereof, as an active ingredient, and an effective amount of at least one polymer containing hydroxyl, carboxyl or sulphite groups or mixtures thereof, as an agent to enhance bioavailability and improve permeability. According to another embodiment of the present invention, a process for the preparation of solid dosage forms for oral administration such as tablets, capsules and sachets, containing a bisphosphonate, and in particular Alendronate or Risedronate or Ibandronate or a pharmaceutical acceptable salt or derivative thereof as an active ingredient and an effective amount of at least one polymer containing hydroxyl, carboxyl or sulphite groups or mixtures thereof, as an agent to enhance bioavailability and improve permeability, which comprises:

- forming a homogenous mixture by mixing the total quantity of said active ingredient with the total quantity of said at least one polymer containing hydroxyl, carboxyl or sulphite groups or mixtures ;

- Sieving the above mixture through a sieve; - Adding to the sieved mixture the total quantities of at least one optional excipient such as a binder, a filler, a disintegrant, a surfactant, a lubricant and/or a glidant and mixing until uniform, and

- Formulating the resulting mixture in a solid dosage form either by compressing it into a desired tablet form or by filling capsules or sachets.

Further preferred embodiments of the present invention are defined in dependent claims 2 to 10 and 12 to 18.

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

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows the orientation of the carbonyl group in the crosslinked molecule of crospovidone.

Fig. 2 shows the structure of croscarmellose sodium. Fig. 3 shows a schematic representation of an "egg box" structural form.

Fig. 4 shows a schematic representation of hydrogen bond formation between PVP and protein reactive groups.

Fig. 5 shows average plasma values for the composition of Example 1 according to the present invention. Fig. 6 shows average plasma values for the composition of Example 2 according to the present invention.

Fig. 7 shows average plasma values for the composition of Example 3 according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, the terms "bisphosphonate" and "bisphosphonate drug" mean a derivative of bisphosphonic acid known in the art for remodelling bone. Except where noted otherwise, the term "bisphosphonate" also includes a pharmaceutically acceptable salt thereof. Examples of bisphosphonates include, but are not limited to, alendronate, risedronate, ibandronate, etidronate, clodronate, pamidronate, tiludronate, ibandronate, zoledronate, incadronate, olpadronate, neridronate, or amidronate. The term "active agent" refers to orally deliverable bisphosphonates. The term "gastrointestinal tract" as used herein relates to the alimentary canal, i.e., that musculo- membranous tube about thirty feet in length, extending from the mouth to the anus.

The term "buccal cavity" means the mouth or oral cavity and is lined with a mucous membrane which is continuous with the integument of the lips and with the mucous lining of the pharynx.

The term "pharynx" relates to the part of the upper gastrointestinal tract which is placed behind the nose, mouth and larynx. It is a mucomembraneous tube about 4 inches in length and posteriority with the esophagus and is composed of a mucous coat, a fibrous coat, and a muscular coat.

The term "esophagus" as used herein is a muscular canal about nine inches long extending from the pharynx to the stomach. The esophagus has three coats; and internal mucous coat surrounding the lumen, a middle alveolar coat and an external muscular coat.

The term "stomach" as used herein means that part of the gastrointestinal tract between the esophagus and the small intestine.

The term "pharmaceutical composition" means an oral dosage form comprised of a safe and effective amount of a bisphosphonate and pharmaceutically-acceptable excipients.

The phrase "safe and effective amount", as used herein means an amount of a compound or composition high enough to significantly positively modify the symptoms and/or condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio).

The term "pharmaceutically-acceptable excipients" as used herein includes any physiologically inert, pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of the particular active ingredient selected for use. Pharmaceutically-acceptable excipients include, but are not limited to, polymers, resins, plasticizers, fillers, lubricants, binders, disintegrants, solvents, co-solvents, buffer systems, surfactants, preservatives, sweetening agents, flavouring agents, pharmaceutical grade dyes and pigments.

The term "oral dosage form" as used herein means any pharmaceutical composition intended to be administer to the stomach of an individual via the mouth of said individual.

The term "functional coating" as used herein relates to a film coating which affects the absorption of the active ingredient and/or minimizes the irritation and the GI toxicity. The coating may be applied to a compressed tablet, beads, granules, or particles of active ingredient that are compressed into tablets and the coating chosen must be compatible with the particular active ingredient selected.

The terms "risedronate" and "risedronate active ingredient" include risedronate (the bisphosphonate compound 3-pyridyl-l-hydroxyethylidene-l,l-bisphosphonic acid), risedronate salts, and risedronate esters, or any mixture thereof. Any pharmaceutically-acceptable, non-toxic salt or ester of risedronate may be used as the risedronate active ingredient in the novel oral dosage forms of the present invention. The salts of risedronate may be acid addition salts, in particular the hydrochloride, but any pharmaceutically-acceptable, non-toxic organic or inorganic acid salt may be used. In addition, salts formed with the phosphonic acid group may be used, including, but not limited to alkali metal salts (K, Na) and alkaline earth metal salts (Ca, Mg) where the Ca and Na salts are being preferred. Particularly, other esters of risedronate which are suitable for use as the active ingredient herein are straight chain or branched chain Cl -C 18 alkyl esters, including, but not limited to, methyl, ethyl, propyl, isopropyl butyl, isobutyl, amyl hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, and stearyl; straight chain or branched C2-C18 alkenyl, esters, including but not limited to vinyl, alkyl, undecenyl, and linolenyl; C3-C8 cycloalkyl esters, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; aryl ester, including, but not limited to phenyl, toluyl, xylyl, and naphthyl; alicyclic esters, including, but not limited to, menthyl; and aralkyl esters, including, but not limited to benzyl, and phenethyl.

The term "alendronate" as used herein, denotes the bisphosphate compound 4-amino-l- hydroxybutylidene-l,l-bisphosphonic acid and its pharmaceutically-acceptable salts, i.e. monosodium trihydrate. For the purposes of the present invention, a pharmaceutical composition comprising an active ingredient (bisphosphonic acids e.g. Alendronate, Risedronate or Ibandronate or salts thereof) is considered to be "stable" if said ingredient degradates less or more slowly than it does on its own and/or in known pharmaceutical compositions. The active ingredient (a bisphosphonate e.g. Alendronate, Risedronate or Ibandronate or a pharmaceutical acceptable salt thereof) contained in a dosage form is "enhanced bioavailable", if when administered in a dosage form is released from the dosage form, absorbed and subsequently reaches higher concentration levels in plasma than the marketed products containing the same quantity of the same active ingredient and intended for the same use.

Although the pharmaceutical composition may be in various forms, the preferred solid forms are tablets, capsules and caplets.

It has been surprisingly found that the object of the present invention is achieved by employing polymers containing carboxyl, hydroxy! or sulfite groups (-COOH, -OH, -SO₃H) such as crosscarmellose sodium and PVP in order to enhance the bioavailability of the active ingredient.

As already mentioned bisphosphonate such as Risedronate or Ibandronate have very poor water solubility thus reflecting in poor bioavailability of the active substance.

Moreover, bisphosphonate compounds get difficultly absorbed through the digestive tract. In general, the main factors affecting the absorption process are the passive diffusion through the transcellular pathway, which is the main uptake mechanism through mucosal membranes and the P-glycoprotein mediated e-flux, active transport, transcytosis, paracellular pore pathway.

According to the well accepted "rule of 5" introduced by Lipinski in 1997 (Lipinski et al, "Experimental and computational approaches to stimate solubility and permeability in drug discovery and development settings", Adv. Drug. De. Rev., 1997 23:3, 3-25), poor absorption or permeation is more likely when: • There are more than 5 H-bond donors (expressed as the sum of -OH and -NH).

• There are more than 10 H-bond acceptors (expressed as the sum of -O and -N).

• The molecular weight is over 500 (MW>500)

• The log P is over 5

• The compound classes that are substrates for biological transporters are exceptions to the rule. Risedronate has a molecular weigh 283,112 (base), which increases for the different salts. The reason for the low permeability is due to formation of the drug- insoluble complexes formed either with metal ions contained in food, or with the mucus components of the digestive tract, particularly bivalent metal ions such as calcium ions or proteins. The low permeability of the molecule's complexes with bivalent metal ions (such as calcium) may also be allocated to the further increase of the molecular weight of the complex. The complexation of Risedronate with the polymers according to the composition of the present invention results in a reversible blocking of the hydrogen donors and acceptors and so they are unable to interact with bivalent metal ions due to stereochemical inhibition. This inhibition takes place throughout the mucosal layer, until the polymer reaches the mucosal membrane. At this point, when the site of absorption in reached, the polymer that possesses also mucoadhesive properties interacts with the mucosal membrane. Due to topical concentration difference and diffusion gradient, Risedronate molecules are absorbed through diffusion. As a result the concentration of Risedronate in the fluids that are in contact with the membrane and the polymer is topically decreased. This way the complex releases additional amounts of Risedronate, as the equilibrium between the complexed and free risedronate must remain constant.

This effect is being decreased when the molecule is crosslinked, and the bond forming compound is on the main molecular chain of the polymer. For this reason, crospovidone does not have a major effect on bioavailability enhancement, as the carbonyl group is oriented toward the main chain (Fig. 1).

On the contrary, molecules which form hydrogen bonds and are not crosslinked, or molecules that are crosslinked but the hydrogen bond forming groups are oriented towards the outer part of the main chain, such as croscarmellose sodium (Fig.2) can provide complexes that enhance the absorption and bioavailability of Risedronate. Croscarmellose sodium has additional hydrogen bond forming groups when compared to crospovidone, while the orientation of said hydrogen bonds enables the development of such bonds.

Polymers containing carboxyl, hydroxyl or sulphite groups (-COOH, -OH, -SO₃H), when incorporated in a pharmaceutical composition comprising bisphosphonate compound according to the present invention, allow the drug substance to permeate the mucous layer and the mucous membrane without forming insoluble complexes in the digestive tract.

It appears that the polymers containing carboxyl, hydroxyl or sulphite groups in solution form, by reaching the mucous layer and/or mucous membrane before permeation of the drug, prevent the components contained in said layer/membrane from interacting with the drug and thus inhibit the formation of insoluble complexes and so leads to enhanced drug permeability of the epithelial cells. Polymers containing carboxyl, hydroxyl or sulphite groups can easily form complexes with bivalent metal ions such as calcium and therefore prevent the drug from forming insoluble complexes with these metal ions in the digestive tract. Experiments involving equilibrium dialysis of these polymers have shown that selective binding with alkaline earth metals ion such as Ca²⁺ and Mg²⁺ can be formed as shown in Fig. 3. This high selectivity indicates that chelation causes formation of structural forms known as "egg box". When polymers containing carboxyl, hydroxyl or sulphite groups are incorporated in a pharmaceutical composition containing a bisphosphonate compound or a pharmaceutical acceptable salt thereof according to the present invention, the novel composition results an enhanced absorption of the bisphosphonate compound.

Moreover, the use of polyvinylpyrrolidone in the pharmaceutical composition according to the present invention prevents the bisphosphonate from forming insoluble complexes with the proteins of the digestive tract, leading also to enhance drug permeability of the epithelial cells.

Polyvinylpyrrolidone is a water-soluble tertiary amide and a strong Lewis base. Due to its polar groups it is a powerful proton acceptor, easily creating hydrogen bonding interactions with other polymers or small molecules, whereas the latter are proton donors. This effect enhances polymer miscibility since hydrogen bonding induces a negative, favorable enthalpic contribution to the Gibbs free energy of mixing. In the present invention it is claimed that such hydrogen bonds are possible to be formed with protein >NH and >C=O reactive groups (Fig. 4).

Consequently, the use of polyvinylpyrrolidone in the pharmaceutical composition according to the present invention also enhances the bisphosphonate absorption in vivo by preventing interaction of the bisphosphonate compound with the proteins of the digestive tract.

Moreover, any excipient may optionally be added to the above composition, provided that they are compatible with the active ingredient of the composition, in order to overcome problems associated with unfavorable pharmacotechnical characteristics of these substances, and in order to increase the stability of the drug and the self-life of the pharmaceutical product, and provide a product exhibiting excellent bioavailability.

The present invention can be applied in the formulation of tablets, capsules, caplets, sachets or other solid dosage forms for oral or sub-lingual administration of an active ingredient having solubility and bioavailability problems.

Furthermore, it is possible to prepare dosage forms of different strength using appropriate quantity of the same composition, thereby limiting the cost of production and minimizing the number, and consequently the cost, of clinical studies required for the approval of the product by the authorities. The manufacturing process for preparation according to the present invention is simpler and inexpensive in comparison to any other conventional method.

Therefore, in a first embodiment, the present invention provides a pharmaceutical composition comprising from about 0.1% to about 99%, of bisphosphonate and from about 1% to about 99.9% pharmaceutically-acceptable excipients. For risedronate the composition comprises, preferably 0.25% to 40%, preferably from about 0.3% to about 35% of a risedronate active ingredient and from about 60% to about 98%, preferably from about 70% to about 95 % of pharmaceutically-acceptable excipients. Polymers containing carboxyl, hydroxyl or sulphite groups include, but are not limited to, croscarmellose sodium, carbopol, carboxymethyl cellulose sodium, sodium alginate, dextran, starch, carrageenan, aspartame, crospovidone, dextrose, docusate sodium, glycerin, hypromellose phthalate, lecithin, poloxamer, PEG, polysorbates and sucrose. Preferred polymers containing carboxyl, hydroxyl or sulphite groups are Croscarmellose sodium, carbopol, carboxymethyl cellulose sodium, sodium alginate, dextran, starch and carrageenan. Most preferred polymers containing carboxyl, hydroxyl or sulphite groups are croscarmellose sodium, carbopol and carrageenan. The preferred pharmaceutical compositions are in the form of solid dosage forms for oral or sublingual administration such as tablets, capsules, caplets, troches, pastilles, pills, lozenges and the like, in all shapes and sizes, coated or uncoated.

All percentages stated herein are weight percentages based on total composition weight, unless otherwise stated. Another embodiment of the present invention is the use of the direct compression process for the preparation of solid dosage forms for oral administration such as tablets, capsules and sachets containing bisphosphonate such as Alendronate or Risedronate or Ibandronate or salts thereof, which is one of the most economical methods. Said process of the present invention for the preparation of solid dosage forms containing Alendronate or risedronate or Ibandronate or salts thereof as an active ingredient comprises:

- forming a homogenous mixture by mixing the total quantity of the active ingredient with the total quantity of at least one polymer containing hydroxyl, carboxyl or sulphite groups, as an agent to enhance bioavailability;

- sieving the above mixture on a sieve, and subsequently - adding to the sieved mixture the total quantities of at least one optionally excipient such as a filler, a binder, a disintegrant, a glidant, a lubricant and surfactant and mixing until uniform, and

- formulating the resulting mixture in a solid dosage form either by compressing it into a desired tablet form or by filling capsules or sachets. Further, said tablets can be film coated with a pH dependent polymer.

The pharmaceutical compositions of the present invention may also contain one or more additional formulation ingredients selected from a wide variety of excipients. According to the desired properties of the composition, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparation of solid dosage form compositions.

Such ingredients include, but are not limited to, diluents, binders, compression aids, disintegrants, surfactants, antioxidants, glidants, lubricants, flavors, water scavengers, colorants, sweetener, coating agents and preservatives.

The optional excipients must be compatible with the bisphosphonate or the salt thereof so that it does not interfere with it in the composition.

Fillers may be, for example, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose maltodextrin, maltitol.

Binders may be, for example, acacia mucilage, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyhnethyl cellulose, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch, sucrose.

Disintegrants may be, for example, alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, guar gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium laulyl sulfate, sodium starch glycolate, starch, pregelatinized starch and ion exchange resins.

Surfactants may be, polyoxyethylene-polyoxypropylene co-polymers and block co-polymers, commercially available as Pluronic™ or Poloxamer™, ethoxylated cholesterins, commercially available as Solulan™ vitamin derivatives, e. g. vitamin E derivatives such as tocopherol polyethylene glycol succinate (TPGS), sodium dodecylsulfate or sodium laurylsulfate; a bile acid or salt thereof, for example cholic acid, glycolic acid or a salt.

Glidants may be, for example, calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide.

Lubricants may be e.g. polyethylene glycol 4000, polyethylene glycol 6000, sodium lauryl sulfate, starch, talc, stearic acid, colloidal silicon dioxide, zinc stearate, hydrogenated castor oil, sodium stearyl fumarate.

The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention:

EXAMPLES

Example 1: coated tablets of Risedronate:

Tablets of the above formulation were prepared according to the following manufacturing process: Risedronate sodium hemipentahydrate, Starch 1500, MCC, PVP, croscarmellose and crospovidone were admixed to complete homogeneity. The above mixture was sieved. The final mixture was then compressed directly into tablets in a tableting machine with round punches of a 10mm diameter. The tablets were coated with Eudragit and packed into blisters of PVC-PVDC.

The produced tablets were tested for hardness, friability, disintegration, and water content. All tests were performed according to European Pharmacopoeia 5.1 and were well within the specifications.

One of the most critical pharmacotechnical tests is the dissolution test as it is strongly correlated with the bioavailability of the product. For the dissolution method a Paddle Apparatus was run at

50rpm, in 900 ml HCL 0.01N, buffer 4.5 and buffer 6.8, and showed more than 70% dissolved in 10 min and more than 80% in 15 min for HCL 0.0 IN and buffer 4.5 but different behavior for buffer 6.8. TABLE 1 : Dissolution profile of the composition of Example 1

It is obvious that the composition of Example 1 does not allow the release of the drug at more than pH 5 (mouth, pharynx and esophagus area), but allows the release of the drug at less than pH 5 (stomach area). Example 2 : coated tablets of Risedronate:

Dissolution test in 900 ml HCL 0.01N, buffer 4.5 and buffer 6.8, 50 rpm Paddle Apparatus showed more than 70% dissolved in 10 min and more than 80% in 15 min for HCL 0.01N and buffer 4.5 but different behavior for buffer 6.8 TABLE 2: Dissolution profile of the composition of Example 2

It is obvious that the composition of Example 2 does not allow the release of the drug in environment at more than pH 5 (mouth, pharynx and esophagus area), but allows the release of the drug in environment of less than pH 5 (stomach area).

Example 3: coated tablets of Risedronate:

Tablets of the above formulation were prepared according to the following manufacturing process: Risedronate sodium hemipentahydrate, Starch 1500, MCC and crospovidone were admixed to complete homogeneity. The above mixture was blend with the amount of water. The produced granule was dried and milled. The milled mixture was then mixed with Mg stearate for about 5 minutes. The final mixture was then compressed directly into tablets in a tableting machine with round punches of a 10mm diameter. The tablets were coated with opadry white and packed into blisters of PVC-PVDC.

Dissolution test in 900 ml water, HCL 0.0 IN, buffer 4.5 and buffer 6.8, 50 rpm Paddle Apparatus showed more than 70% dissolved in 10 min and more than 80% in 15 min. TABLE 3: Dissolution profile of the composition of Example 3

As it is shown in Table 3 the composition of Example 3 has the same dissolution behaviour at all pH values.

Another object of the present invention was to prepare a pharmaceutical composition that is stable, said active ingredient does not degradates for a long period of storage time. For this reason, prior to the clinical trials, the composition of Example 1 was packed in PVC/PE/PVDC Aluminum blisters and exposed to normal (25°C±2°C/60%±5% RH), intermediate (30°C±2°C/65%±5% RH) and accelerated (40°C±2°C/75%±5% RH) stability studies according to the current ICH guidelines. The stability results after six months have shown that the Risedronate composition of Example 1 remains stable when croscarmellose and PVP are incorporated in the formulation.

The results have shown a good stability of the product and compatibility between the drug substance and the excipients proposed by the present invention. The excellent results regarding the physicochemical characteristics, the excellent stability of the product as well as the simple and economic manufacturing process indicate the advantages of the present invention relative to the commonly used methods and excipients for the formulation of bisphosphonate such as Risedronate or Ibandronate or Alendronate.

The compositions described above were investigated for their scalability, while a process validation was performed in order to prove the repeatability and accuracy of the manufacturing process and the proposed formulations. The validation process showed that the compositions and the manufacturing process are suitable in order to provide a repeatable and high quality product.

According to another aspect of the present invention, the active substance should remain in crystalline form after compression. It has been confirmed by X-RD analysis, that all the recorded characteristic peaks of Risedronate sodium were unchanged after 6 months storage in accelerated conditions (40 ⁰C and 75 % RH).

The crystal properties remain also unchanged after six months in the same conditions when the mixture is incorporated in a pharmaceutical composition with other excipients.

Tablets of composition 1 have the main peaks obtained at approximately 20=9.15, 12.55, 20.05, 24.85, 31.30, 36.55 degrees which are also found in the X-RD analysis of the active ingredient

Risedronate sodium.

The bioavailability and pharmacokinetic profile of all three compositions of the present invention were determined in "in vivo" single-dose studies. A single-dose study was conducted in 100 healthy volunteers under fasting conditions using a composition prepared with Risedronate sodium hemipentahydrate according to Example 1.

The reference compound was a 35mg Risedronate sodium tablet (Actonel 35mg) that consists of the active ingredient, Crospovidone, HPC, HPMC, lactose monohydrate, Mg stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide, titanium dioxide (Composition

B).

Each patient received a single oral 35mg dose of Composition 1 according to Example 1 and a tablet of Composition B equal to 35 mg of active ingredient, at different times. Blood samples were taken at different times and the plasma concentrations of Risedronate were determined. In the pharmacokinetic analysis of composition 1 according to Example 1, Risedronate is measured. Table 4 shows the main pharmacokinetic parameters obtained from the test.

TABLE 4: Pharmacokinetic analysis of composition 1 versus reference product (B)

wherein:

C max = (peak concentration) is the highest concentration reached by the drug in plasma after dosing;

AUCo-_t =(area under the curve) is the total area under the time - plasma concentration curve, from time 0 to the last measurable concentration, as calculated by the linear trapezoidal method; it represents a measure of the bioavailability of the drug.

AUCo-i_nf -(area under the curve) is the total area under the time- plasma concentration curve from time 0 to infinity. AUCinf is calculated as the sum of AUC 0-t plus the ratio of the last measurable plasma concentration to the elimination rate constant.

Consequently, it has been found that composition 1 of Example 1 has a relative bioavailability of approximately 148% compared to the marketed Risedronate sodium 35 mg tablet (Fig. 5).

Moreover, a single-dose study was conducted in 18 human volunteers under fasting conditions in a randomised two-way crossover study, comparing the 23 mg dosage form of composition of

Example 2 with the 35 mg dosage form of composition B. Plasma samples were removed and tested for Risedronate at intervals.

In the pharmacokinetic analysis of the 23 mg composition 2 according to Example 2, the

Risedronate is measured. Table 5 shows the main pharmacokinetic parameters obtained from the test. TABLE 5: Pharmacokinetic analysis of composition 2 versus reference product (B)

Consequently, it has been found that composition 2 (23 mg tablet) has a relative bioavailability of 103% compared to the marketed Risedronate sodium 35 mg tablet (Fig. 6). Further, a single-dose study was conducted in 110 human volunteers under fasting conditions in a randomised two-way crossover study, comparing the 35 mg dosage form of composition of Example 3 with the 35 mg dosage form of composition B. Said composition does not comprise any of the polymers used in the composition 1 and 2, namely no croscarmellose, no PVP, no Eudragit as coating. Plasma samples were removed and tested for Risedronate at intervals.

In the pharmacokinetic analysis of the composition 3 according to Example 3, Risedronate is measured. Table 6 shows the main pharmacokinetic parameters obtained from the test.

TABLE 6: Pharmacokinetic analysis of composition 3 versus reference product (B)

Consequently, it has been found that composition 3 (35 mg tablet) has a relative bioavailability of 91% compared to the marketed Risedronate sodium 35 mg tablet (Fig. 7).

The in vivo results indicate that concentration level of the active substance in plasma for compositions 2 and 3 is approximately 103% and 91% of the level of the reference product, respectively. Surprisingly, composition 1 showed 148% increase in plasma concentration in comparison with the reference product. Composition 1 showed an enhanced bioavailability in comparison with the marketed reference product.

Moreover, the in vivo results with respect to composition 2 give the possibility to manufacture a pharmaceutical composition with smaller quantity of active ingredient than the reference product but with the same effect resulting in better patient compliance and less side effects.

As it can be seen from the pharmacokinetic results and figures 5, 6 and 7 an enhancement to the absorption of Risedronate is actually achieved by the administration of a pharmaceutical composition according to the present invention.

Another aspect of the present invention is to provide a bisphosphonate composition which reduces the undesirable gastrointestinal adverse effects, hi accordance with the above mentioned objects of the present invention, a composition which enhances the absorption of the bisphosphonate compound can be administrated in order to reduce the undesirable gastrointestinal adverse effects as these effects depend on the dose and the treatment schedule (frequency of dosing).

Moreover, the present invention is directed to a novel film coated oral dosage form comprising a safe and effective amount of a bisphosphonate or a pharmaceutical acceptable salt thereof and pharmaceutically-acceptable excipients according to the present invention.

Said dosage forms avoid or minimize the release of the active ingredient in the mouth, pharynx, and esophagus and protecting the epithelial and mucosal tissues thereof from erosion, ulceration or other like irritation. Particularly preferred are film coated oral dosage forms.

Accordingly, the said dosage forms affect the delivery to the stomach of said human or other mammal of a safe and effective amount of the active ingredient, and substantially alleviate esophagitis or esophageal irritation which occasionally accompanies the oral administration of active ingredients. The novel oral, film coated dosage forms described herein facilitate transit through the esophagus thus effectively delivering the dosage form to the stomach and avoiding or minimizing the undesired release of Risedronate in the mouth, pharynx and/or the esophagus thereby prohibiting the erosion, ulceration or other like irritation of the epithelial or mucosal layers of these tissues.

Accordingly, the said film coating is preferably applied to a compressed tablet which contains particles or granules of active ingredient; however, in the event the particles or granules are themselves film-coated before being compressed into a tablet, then the film coating of the compressed tablet itself is optional. Because of their film coating, these novel dosage forms will avoid the undesirable delivery of the active ingredient to the mucosal and epithelial tissues of the upper gastrointestinal tract, especially the mouth, pharynx and esophagus.

The amount of coating deposited on the tablet is usually in the range of from about 1% to about 6% weight gain with a preferred weight gain of about 3%. The coating can, and usually will, contain a plasticizer. The preferred plasticizers are polyethylene glycol polypropylene glycol and PVP. The preferred amount of plasticizer is from about 15% to about 40% with respect to the film-forming polymer, with the most preferred level of about 30%.

The pH value of the mouth is 6.78±0.04, while the pH value of pharynx and esophagus is approximately 5.5. Thus, preferred polymers for film-coating are pH dependent, namely said plymers are soluble at pH less than 5. Particularly preferred pH dependent polymers are selected from the group consisting of acrylic resins, polyvinylpyrrolidone, polymethacrylates, Starch, PVA, Alginate physical cross linked with CaCl_2, Chitin and Chitosan and their graft, block and random copolymers with Acrylic acid.

Consequently, the novel formulation of the present invention enhances the absolute bioavailability of bisphosphonates or pharmaceutical acceptable salts thereof. The same amount of the bisphosphonates can be given with or without food, with hard water and with calcium.

Moreover, the active ingredient contained in the novel formulation of the present invention can be reliably delivered to the stomach thereby avoiding the undesirable exposure of the active in the mucosal and epithelial tissues of the mouth, pharynx, and/or esophagus. Said dosage forms render the active ingredient readily available for absorption from the stomach and, there is substantially no contact of the active ingredient upon the epithelial and mucosal tissues of the mouth, pharynx, or esophagus. Any film-coating which is soluble in the gastric contents pH < 5 can be used in the practice of the present invention.

Thus the presence of two polymers in the core and one polymer in the film coating, in combination with a metal ion free composition are responsible for the enhanced bioavailability of the Risedronate composition according to the present invention. While the present invention has been described with respect to the particular embodiments, it is 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

-1-CLAIMS

1. A pharmaceutical composition for oral administration comprising a bisphosphonate, and in particular Risedronate or Alendronate or Ibandronate or a pharmaceutical acceptable salt or derivative thereof, as an active ingredient, and an effective amount of at least one polymer containing hydroxyl, carboxyl or sulphite groups or mixtures thereof, as an agent to enhance bioavailability and improve permeability.

2. The pharmaceutical composition according to claim 1 , wherein said at least one polymer is croscarmellose sodium.

3. The pharmaceutical composition according to any preceding claim, wherein said bisphosphonate is Risedronate or a pharmaceutical acceptable salt or derivative thereof.

4. The pharmaceutical composition according to any preceding claim, wherein it further comprises a binder such as PVP.

5. The pharmaceutical composition according to any preceding claim, wherein it further comprises at least one optionally excipient selected from the group consisting of diluents, surfactants, binders, disintegrants, lubricants, and glidants.

6. The pharmaceutical composition according to any preceding claim, wherein said composition is in a solid dosage form such as a tablet, capsule or sachet comprising an active ingredient such as Risedronate or Alendronate or Ibandronate or a pharmaceutical acceptable salt or derivative thereof.

7. The pharmaceutical composition according to any preceding claim, wherein it further comprises a functional coating.

8. The pharmaceutical composition according to any preceding claim, wherein said coating is a pH dependent polymer, such as a polymer soluble at pH < 5.

9. The pharmaceutical composition according to any preceding claim, wherein said composition is sustained release.

10. The pharmaceutical composition according to any preceding claim, wherein said composition is immediate release.

11. A process for the preparation of a solid dosage form for oral administration such as a tablet, capsule or sachet containing a bisphosphonate, and in particular Alendronate or Risedronate or Ibandronate or a pharmaceutical acceptable salt or derivative thereof as an active ingredient and an effective amount of at least one polymer containing hydroxyl, carboxyl or sulphite groups or mixtures thereof as an agent to enhance bioavailability and improve permeability, which comprises:

- forming a homogenous mixture by mixing the total quantity of said active ingredient with the total quantity of said at least one polymer containing hydroxyl, carboxyl or sulphite groups or mixtures

Sieving the above mixture through a sieve; -2-

Adding to the sieved mixture the total quantities of at least one optional excipient such as a binder, a filler, a disintegrant, a surfactant, a lubricant and/or a glidant and mixing until uniform, and

12. The process according to claims 11, wherein said at least one polymer is croscarmellose sodium.

13. The process according to claims 11 to 12, wherein said bisphosphonate is Risedronate or a pharmaceutical acceptable salt or derivative thereof.

14. The process according to any preceding claim, wherein said composition further comprises a binder such as PVP.

15. The process according to any preceding claim, wherein said composition further comprises a functional coating.

16. The process according to claim 15, wherein said coating is a pH dependent polymer, such as a polymer soluble at pH < 5.

17. The process according to any preceding claim, wherein said composition is sustained release.

18. The process according to any preceding claim, wherein said composition is immediate release.