Patent Publication Number: US-2006013893-A1

Title: Bisphosphonates inorganic carriers

Description:
BACKGROUND OF INVENTION  
      Considerable research efforts have been conducted on oral sustained and controlled release drug delivery systems. Special attention has been given to regulate the rate of drug release by means of monolithic devices, where the drug is dispersed or included in an inert matrix. One of many such systems involves the intercalation of a drug in a lamellar host lattice. Several natural and synthetic clays having either cationic or anionic replaceable ions by simple exchange methods are ideal carriers for charged drug molecules.  
      For example bentonite can exchange with cationic drugs, and hydrotalcite can exchange with anionic drugs  
      Bentonite and hydrotalcite are only two examples of clays that form intercalated drug delivery systems.  
      This invention deals with new and novel compositions and formulations of bisphosphonates with hydrotalcite-like clays resulting in lamellar host lattice intercalated drug delivery systems. Bisphosphonates are a family of bioactive drugs that have been used in the management of disorders of calcium and bone metabolism for the past three decades. The therapeutic potential of bisphosphonates is due to their patent inhibition of osteoclast mediated bone resorption. By varying the substuents on the methylene group located between two phosphonic acid groups many different derivatives have been synthesized, and several have been commercialized. Neutral methylene functionalities include; hydroxy, alkyl, aryl; basic functionalities include amino, heterocyclic; acid functionalities include carboxylic acid, sulfonic acid.  
     SUMMARY OF THE INVENTION  
      This invention is based on intercalation chemistry involving bisphosphonates and hydrotalcite-like anionic clays. The various layered materials useful as the host for the anionically charged bisphosphonates are collectively known as layered double hydroxides. These are part of a large class of materials closely related to the mineral hydrotalcite and represented by the general formula [M 2+   1-x M 3+   x (OH) 2 ]A n   x/n .yH 2 O; or [M 1+ M 3+   2 (OH) 6 ]A n−   x/n .yH 2 O; where M 1 =Li, Na, K, Rb or Cs; M 2+ =Ca, Mg, Mn, Co, Ni, Cu, Zn, and Cd; and M +3 =Cr, Fe, Al, Ga, In, Mo, A maybe an organic anion, e.g., bioactive bisphosphonate, or an inorganic anion such as PO 4   −3 , NO 3   − ; Cl − , Br − ; I − , ClO −   4 , SO 4   −2 , or CO 3   −2 , the value of x is usually between 0.2 and 0.33 related class of materials and having in general, a very similar intercalation chemistry are the hydroxy double salts of the general formula; (M 2+ ) 5  (OH) 8 (A n−n ) 2/n yH 2 O or (M +2 ) 2 (OH) 3 .(A n− ) 1/n .yH 2 O; wherein M is typically Zn, Cu, or Ni. These remarkable materials are closely related to the mineral brucite, Mg (OH) 2 , which has a layered structure consisting of sheets of edge-sharing Mg (OH) 6  octahedra. The hydrotalcite structure is derived from brucite by substitution onto the cation sublattice, and the subsequent uptake of the anion into the interlayer region to preserve charge neutrality.  
      Hydrotalcite is effective against the treatment of ulcers. It is believed that the high anti-peptic activity of hydrotalcite may be due to its ability to absorb the negatively charged pepsin onto its positively charged surface. Hydrotalcite is also capable of buffering the pH of the stomach at about 4 for a long time. Thus gastric juice is maintained at a pH that is neither too acidic for high pepsin activity nor too alkaline to trigger the acid rebound. Moreover, the rate of hydrochloric acid neutralization by hydrotalcite increases with pepsin concentration.  
      A comparison of different antacid compounds (at doses with at least comparable neutralizing capacity) also demonstrated that the hydrotalcite displays the lowest intestinal absorption and does not increase the level of aluminum in the serum (van der Voet et al., Clinical Toxicology, 24 (1986-87) p. 545).  
      The dissolution of any Al +3  ions is negligible as reported by van der Voet in the serum of a patient taking hydrotalcite formulations. If need be, the exchangeable carbonate can be replaced by phosphate, or sodium phosphate can be part of the total dosage, and any Al +3  ions will react with phosphate to yield a very water insoluble aluminum phosphate.  
      A unique aspect of our invention involves the anionic exchange capability of hydrotalcite, whereby certain non-steroidal anti-inflammatory drugs or NSAID&#39;s, which are able to form an anion can be administered along with a bisphosphonate simultaneously.  
      Examples of some, not all inclusive, NSAID&#39;s are aspirin, ibuprofren, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofan, ketofolac, mefenamic acid, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin and the like.  
      Other bioactive molecules, capable of forming an exchangeable anion with the hydrotalcite anion, are vitamins C and E, thereby resulting in synergy. Both vitamins can be intercalated with hydrotalcite and hydrotalcite like clays. Vitamins C and E are known to benefit the maintenance of healthy bone structure and growth. For example vitamin C functions to help maintain collagen, a protein necessary for forming skin, ligaments, teeth, and bones. Vitamin E derivatives have beneficial effects on bone calcium in adrenalectomized animal studies (S. Ima-Nerwana, J. Med. Food, 2004, Spring 7(1)45-51).  
      It is also known that patients with peptic disorders e.g., peptic ulcers generally have low leucocyte levels of ascorbic acid. This is also true for patients with gastroduodenal problems. Thus the availability of Vitamin C would help to alleviate these conditions.  
      Amino carboxylic and amino phosphonic chelating agents like EDTA can also be incorporated as an anion.  
      Obviously, several biological actives could be administered using the teachings of this invention, provided they have a therapeutic value.  
      Any bioactive bisphosphonate useful for the treatment of osteoporosis can be affixed to hydrotalcite-like anionic exchange clay via a sodium salt of the drugs phosphonate function. The resulting phosphonate anion can exchange with the anions in between the lamellar lattice. Obviously other water-soluble anionic salts are also operative according to the teachings of this invention. Suitable bisphosphonates are pamidromate, ibandronic acid, ibandronate, risedronate, cimadronate, clodronate, etidronic acid, neridronate, olpadronate, piridronate, tiludronate, zolendronate, icadronate, and pharmaceutically acceptable salts thereof.  
      The anionic exchangeable clays of this invention, most preferred are hydrotalcite-like clays, which has been described in the specifications of this application. The exchangeable anion can be chloride, carbonate, sulfate, nitrate or other non-coordinated anions, which are easily displaced by bisphosphonate anions or the free acid.  
      While the hydrotalcite-like clays can vary within theoretical limits the composition of the synthetic material used in these experiments had the formula: Mg0.67 Al 0.33 (OH) 2  Cl0.33·0.6H 2 O (ref. Clays Clay Miner, 1983; 31; 305-311 and references cited in article). The ion exchange capacity is 3.9 meq/gram. It is understood by those skilled in the fields of chemistry that other compositions, as described in this invention, can be successfully substituted to achieve teachings of this technology.  
      With respect to the drug release rates, fortunately there are several modifications, which can be utilized to extent the delivery of the bisphosphonate to assure better bioavailability beyond the drug-hydrotalcite composition. One such modification is to coat said composition with a water-soluble or hydrocolloid polymeric substance, e.g., cellulose, hydroxyalkylcellulose, corn starch, gum arabic, alginate, polyvinyl alcohol, carboxymethylenecellulose, polyvinyl pyrollidione, acrylic resins, polyethylene glycol waxes, carrageenan cellulose acetate phthalate and the like. These specific examples are just a few known in the pharmaceutical industry useful for enteric coatings.  
      A second approach to extent the release of the bisphosphonate-hydrotalcite is achieved by co-administering a mixture of unloaded hydrotalcite with the drug-clay composition. In general the weight ratio of drug-clay to clay was 1:1.1 to 1:2 w/w. By changing variables such as loadings, particle size and ratios it is possible to further optimize the rate of release of the bisphosphonate. Enteric coatings are also useful in the final formulation in the administration of the drug.  
      Yet another option for controlling the release can be used to carry out the teachings of this invention involves the physical admixture of a bisphosphonate and a hydrotalcite clay. As with the other methods of changing the release of the bisphosphonate enteric coatings are an option.  
      The bisphosphates-hydrotalcite clays of this invention are preferably those for internal administration, e.g., unit dosage forms such as oral, vaginal and rectal formulations, e.g., tablets, capsules, syrups, drops or suppositories. It is also possible to use stable slurries of these formulations that are used for injections.  
      The novel pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by conventional mixing, granulating, confectioning, dissolving or lyophilizing method.  
      Suitable carriers are in particular fillers such as sugar, for example lactose, saccharose, mannitol, or sorbitol, cellulose or derivatives thereof and/or calcium phosphates and also binders such as starches and/or water-soluble polymers or hydrocolloids. The latter can also be used as an outer coating to achieve various degrees of control release. Other adjuncts useful as glidants and lubricants like silica, talc, stearic acid/derivatives thereof, are also used for the formulation of these drugs.  
      Gelatin capsules are yet another form of delivery. Plasticizers like glycerol, propylene glycol, low molecular weight polyethylene glycols or sorbitol are useful in the preparation of said capsules.  
      The teachings of this invention offer several advantages over the prior art in terms of administrating an effective amount of a bioactive bisphosphonate to manage disorders of calcium and bone metabolism. The therapeutic potential of bioactive bisphosphonates is due to their potent inhibition of osteoclast mediated bone resorption. The dosage forms prohibit the exposure of the bisphosphonates to the epithelial and mucosal tissue of the buccal cavity, pharynx, esophagus, and stomach and thereby protects said tissues from erosion, ulceration or other like irritation. According, the bisphosphonates-hydrotalcite dosage forms effect the delivery to the lower intestinal tract of said human or other mammal of a safe and effective amount of the bisphosphonate drugs, and substantially alleviate the esophagitis or esophageal irritation which often accompanies the oral administration of bisphosphonates active ingredients.  
      Another advantage of this invention is the prolonged release of the bisphosphonate from the hydrotalcite, or the hydrotalcite matrix tablet whereby increasing they bioavailability of the active drug.  
      Toxicity is also another advantage in the dosage forms of this invention by virtue of the inert and non-toxic usage of hydrotalcite in the delivery of a bisphosphonate. Hydrotalcites are not metabolized and it is readily removed from the body.  
      Another advantage of the dosage forms of this invention is the ability of the drug-clay composition to mask the taste of bioactive bisphosphonates. This complex passes unchanged through the gastric system into the intestinal tract.  
      Experimental  
      Well crystallized Mg0.67 Al0.33 (OH) 2  Cl0.33.0.4 H 2 O was synthesized as described in Eur. J. Inorg. Chem. 1998; 10:1439-1446. Alendronate sodium trihydrate and risedronate sodium was purchased from a Chinese source.  
      Intercalation of the Bioactive Bisphonates with Hydrotalcite-Like Clay with Chloride Exchangeable Anions.  
      Intercalation reactions were performed by equilibrating hydrotalcite and the bisphosphonate in a aqueous ethanol mixture (50:50 v/v ) at 60° C. for 3 days in a molar ratio of 1:2. After cooling, the mixture was centrifuged at 5000 rpm for 5 minutes, then the residue was washed 3 times with degassed water and finally dried at room temperature.  
      When using either the sodium salts of alendronate or risedronate near complete intercalation resulted, which approached about 3.7 meq/gram.  
      Generalized Matrix Tablet  
      A matrix tablet is a compressed dosage form containing the appropriate bisphosphonate (from about 70-150 mg bisphosphonate)-hydrotalcite clay, matrix agent, plus fillers, lubricants and excipients. Using water-soluble Methocel F as a rate-controlling polymer, the matrix may be tableted by direct compression or conventional wet granulation. Water permeates into the tablet causing the gel layer to become thicker. Soluble drug diffuse out of the gel layer at a rate controlled by the gel viscosity. With soluble drugs, the primary release mechanism is by diffusion through the gel layer. The amount of Methocel F in the matrix tablet is about 25 wt. percent.  
      Formulated Tablets (Using Alendronate Mono-Sodium Trihydrate) 
    
    
     EXAMPLE 1  
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
               
             
            
               
                   
                 Alendronate - hydrotalcite 
                 250 mg  
               
               
                   
                 Corn starch 
                 25 mg 
               
               
                   
                 Magnesium stearate 
                 10 mg 
               
               
                   
                 Methocel F 
                 85 mg 
               
               
                   
                 Lactose 
                 100 mg  
               
               
                   
                   
               
            
           
         
       
     
     EXAMPLE 2  
                                                            Alendronate - hydrotalcite   200 mg            Lactose   25 mg           Allodial silica    5 mg           Corn starch   30 mg           Methocel F   70 mg           Magnesium stearate    5 mg                        
 Overall this invention advances the therapeutic treatment of osteoporosis by disclosing a new control release system with biological bisphosphonate and optionally include other synergistic additives. 
 
 Advantages Include: 
          Control release     Improved bioavailability     Reduced irritation     Mask bitter taste     Incorporate analgesic agents, amine narcotics, vitamins or pro-vitamins, hormones, and/or neutraceuticals