Recent patents on oral combination drug delivery and formulations.

Oral combination drug delivery systems have been proven to be highly beneficial and vital in the treatment of several dreadful diseases such as cancer, HIV (AIDS) and tuberculosis. Further, pharmaceutical companies have often explored the strategy of combination drug therapy for treating diseases such as diabetes (Type 2), cardiovascular diseases, central nervous system (CNS) disorders, and for treating several other microbial infections. Patenting combination drug delivery systems and formulations has been proven to be very beneficial for the sustainment and growth of pharmaceutical industry. Several pharmaceutical companies have explored this opportunity in extending the life cycle of their blockbuster molecules, and providing additional sources of revenues when the new chemical entity (NCE) discovery is scarce. The article reviews some recent combination formulation patents and patent publications, particularly the US patents and patent applications, relevant to oral delivery of pharmaceuticals. Examples of some oral combination products on the US and worldwide market are presented. Patents and patent applications on combination oral formulations relevant to analgesics (including anti-inflammatory and antipyretics), cardiovascular system (CVS) products, antibacterial and antiviral, and central nervous system (CNS) products are briefly discussed.

Development and evaluation of a pH-dependent sustained release tablet for irritable bowel syndrome.

The overall objective of this study was to develop a pH-dependent sustained release tablet formulation of a model drug, tegaserod maleate (TM), which is a poorly water soluble and acid labile drug in gastric milieu. The formulation's goal was to allow the dosage form to pass through the stomach intact, start disintegrating in the upper small intestine and slowly release the active in a controlled manner. Partition coefficient, contact angle and drug-excipient compatibility were investigated as part of the preformulation studies. A pH-dependent sustained release tablet was prepared using a combination of Eudragit L100 and Eudragit S100. The effects of solubilizer, disintegrant, binder, coating polymer concentration, pore former, and plasticizer on the drug release rate were determined. The results demonstrated that approximately 90% of the drug was released in a sustained release manner in the pH 6.8 phosphate buffer within 12 h while no drug was detected when subjected to drug release studies in 0.1 mol/L hydrochloric acid for 2 h. The drug release mechanism involved stress points and/or pore formation in the coated film. The coated tablets were stable at 40 degrees C/75% RH for 3 months. These results highlighted the feasibility of this coated tablet system containing TM, which may contribute to the successful treatment of irritable bowel syndrome.

Preformulation studies of a prodrug of Delta9-tetrahydrocannabinol.

Preformulation studies were performed on a hemiglutarate ester prodrug of Delta(9)-tetrahydrocannabinol (THC-HG), to facilitate the development of stable formulations by hot-melt methods. The various studies performed included solid-state thermal characterization, pKa, logP, aqueous and pH dependent solubility, pH stability and effect of moisture, temperature and oxygen on solid-state stability. A hot-melt method was utilized to fabricate THC-HG incorporated poly (ethylene oxide) (PEO) matrices and the bioadhesive properties, release profiles and post-processing stability of these matrices were assessed as a function of the polymer molecular weight. The prodrug exhibited a T (g) close to 0 degrees C, indicating its amorphous nature. Thermogravimetric analysis revealed a rapid weight loss after 170 degrees C. The prodrug exhibited a seven-fold higher aqueous solubility as compared to the parent drug (THC). Also, the solubility of the compound increased with increasing pH, being maximum at pH 8. The prodrug exhibited a v-shaped pH-rate profile, with the degradation rate minimum between pH 3 and 4. The moisture uptake and drug degradation increased with an increase in relative humidity. Solid-state stability indicated that the prodrug was stable at -18 degrees C but demonstrated higher degradation at 4 degrees C, 25 degrees C and 40 degrees C (51.6%, 74.5% and 90.1%, respectively) at the end of 3-months. THC-HG was found to be sensitive to the presence of oxygen. The release of the active from the polymeric matrices decreased, while bioadhesion increased, with an increase in molecular weight of PEO.

Chemical stability and bioadhesive properties of an ester prodrug of Delta 9-tetrahydrocannabinol in poly(ethylene oxide) matrices: effect of formulation additives.

The objective of the present research was to stabilize a novel hemiglutarate ester prodrug of Delta(9)-tetrahydrocannabinol (THC), in polyethylene oxide (PEO) polymeric matrices produced by hot-melt fabrication, for systemic delivery of THC through the oral transmucosal route. For this purpose, the influence of pH modifiers and antioxidants employed as stabilizing agents in these matrices was investigated. Based on the stability studies, two final formulations were made, and the stability of the active was assessed in these systems. In addition, the bioadhesive properties of PEO matrices were studied as a function of bioadhesive polymer type and concentration, contact time, drug loading and wetting time. Of all of the polymers investigated, bioadhesion was highest with Carbopol 971p. Bioadhesion increased with bioadhesive polymer concentration and wetting time to a certain level beyond which there was no further contribution. Both the contact time and drug loading influenced the bioadhesion. Severe degradation of the prodrug was observed during storage, even at room temperature (75% at the end of 3 months). Incorporation of the stabilizing agents in the PEO matrices reduced the degradation of the prodrug considerably. Citric acid was the most effective of all of the pH modifiers studied. Among the various antioxidants utilized, degradation was observed least in presence of BHT and ascorbic acid. Only 7.6% and 8.2% of prodrug degraded in these matrices, respectively, as compared to the PEO-only matrices (59.4%) at the end of 3 months at 25 degrees C/60% RH. The prodrug was very stable in both of the final formulations at the end of the 3 months at 40 degrees C/75% RH.

Influence of plasticizers on the stability and release of a prodrug of Delta(9)-tetrahydrocannabinol incorporated in poly (ethylene oxide) matrices.

The objective of this research was to stabilize a heat-labile novel prodrug of Delta(9)-tetrahydrocannabinol (THC), THC-hemiglutarate (THC-HG), in polyethylene oxide (PEO) [PolyOx WSR N-80 (PEO N-80), MW 200,000 Daltons] polymeric matrix systems produced by hot-melt fabrication for systemic delivery of THC through the oral transmucosal route. For this purpose, the effects of processing conditions (processing temperature and heating duration), plasticizer type and concentration and storage conditions on the stability of the prodrug were investigated. The selected plasticizers studied included vitamin E succinate (VES), acetyltributyl citrate (ATBC), triethyl citrate (TEC), triacetin and polyethylene glycol 8000 (PEG 8000). Furthermore, the influence of plasticizer concentration on drug release was also studied. The stability of THC-HG in PEO matrices was influenced by all the aforementioned variables. Films processed at 110 degrees C for 7min were found to be favorable for hot-melt processing with a post-processing drug content of 95%, while significant degradation of THC-HG ( approximately 42%) was observed in those processed at 200 degrees C for 15min. The degradation of the prodrug during hot-melt fabrication and also upon storage was considerably reduced in the presence of the plasticizers investigated, VES being the most effective. Modulation of the microenvironmental pH to an acidic range via incorporation of citric acid in PEO-plasticizer matrices significantly improved the stability of the prodrug, with almost 90% of the theoretical drug remaining as opposed to only 15% remaining in PEO-only matrices when stored at 40 degrees C for up to 3 months. The release of drug from PEO matrices was influenced both by the plasticizer type and concentration. A faster release resulted from water-soluble plasticizers, PEG 8000 and triacetin, and with increasing concentration. However, a slower release was observed with an increase in concentration of water-insoluble plasticizers, VES and ATBC.

In vitro and in vivo evaluation of tegaserod maleate pH-dependent tablets.

The purpose of this study was to prepare tegaserod maleate (TM) pH-dependent tablets and evaluate their advantages as a sustained release delivery system. TM, insoluble in water and unstable in gastric milieu, was formulated into pH-dependent tablets coated with combinations of two methacrylic acid copolymers - Eudragit L100 and Eudragit S100. The influence of core tablet compositions, polymer combination ratios and coating levels on the in vitro release rate of TM from coated tablets was investigated. The optimum formulation was evaluated for in vitro release rate and in vivo bioavailability study on beagle dogs. In addition, physico-chemical properties of the drug, including solubility at different pH and temperatures, and dissociation constant were determined. The results showed that no drug was released in 0.1 mol/L hydrochloric acid within 2h, and about 90% of the drug was released in the pH 6.8 phosphate buffer within 12h in a sustained manner. The pharmacokinetic investigation showed that TM pH-dependent tablets exhibited a sustained plasma concentration, a lag time of approximately 2.3h and a relative bioavailability of 159% compared to plain tablets. A close correlation existed between the in vitro release rate of the pH-dependent system and its in vivo absorption percentage. The results of the present study have demonstrated that the pH-dependent tablet system is a promising vehicle for preventing rapid hydrolysis in gastric milieu and improving oral bioavailability of TM for the treatment of irritable bowel syndrome.

Pharmaceutical applications of hot-melt extrusion: Part II.

The advent of high through-put screening in the drug discovery process has resulted in compounds with high lipophilicity and poor solubility. Increasing the solubility of such compounds poses a major challenge to formulation scientists. Various approaches have been adopted to address this including preparation of solid dispersions and solid solutions. Hot-melt extrusion is an efficient technology for producing solid molecular dispersions with considerable advantages over solvent-based processes such as spray drying and co-precipitation. Hot-melt extrusion has been demonstrated to provide sustained, modified, and targeted drug delivery. Improvements in bioavailability utilizing the hot-melt extrusion technique demonstrate the value of the technology as a potential drug delivery processing tool. The interest in hot-melt extrusion technology for pharmaceutical applications is evident from the increasing number of patents and publications in the scientific literature. Part II of this article reviews the myriad of hot-melt extrusion applications for pharmaceutical dosage forms including granules, pellets, tablets, implants, transmucosal, and transdermal systems.

Pharmaceutical applications of hot-melt extrusion: part I.

Interest in hot-melt extrusion techniques for pharmaceutical applications is growing rapidly with well over 100 papers published in the pharmaceutical scientific literature in the last 12 years. Hot-melt extrusion (HME) has been a widely applied technique in the plastics industry and has been demonstrated recently to be a viable method to prepare several types of dosage forms and drug delivery systems. Hot-melt extruded dosage forms are complex mixtures of active medicaments, functional excipients, and processing aids. HME also offers several advantages over traditional pharmaceutical processing techniques including the absence of solvents, few processing steps, continuous operation, and the possibility of the formation of solid dispersions and improved bioavailability. This article, Part I, reviews the pharmaceutical applications of hot-melt extrusion, including equipment, principles of operation, and process technology. The raw materials processed using this technique are also detailed and the physicochemical properties of the resultant dosage forms are described. Part II of this review will focus on various applications of HME in drug delivery such as granules, pellets, immediate and modified release tablets, transmucosal and transdermal systems, and implants.