ABSTRACT
Telmisartan (TEL, an antihypertensive drug) belongs to Class II of the Biopharmaceutical Classification System (BCS) because of its poor aqueous solubility. In this study, we enhanced the solubility, bioavailability, and stability of TEL through the fabrication of TEL-loaded pH-modulated solid dispersion (TEL pHM-SD) using hot-melt extrusion (HME) technology. We prepared different TEL pHM-SD formulations by varying the ratio of the drug (TEL, 10-60% w/w), the hydrophilic polymer (Soluplus®, 30-90% w/w), and pH-modifier (sodium carbonate, 0-10% w/w). More so, the tablets prepared from an optimized formulation (F8) showed a strikingly improved in vitro dissolution profile (~30-fold) compared to the free drug tablets. The conversion of crystalline TEL to its amorphous state is observed through solid-state characterizations. During the stability study, F8 tablets had a better stability profile compared to the commercial product with F8, showing higher drug content, low moisture content, and negligible physical changes. Moreover, compared to the TEL powder, in vivo pharmacokinetic studies in rats showed superior pharmacokinetic parameters, with maximum serum concentration (Cmax) and area under the drug concentration-time curve (AUC0-∞) of the TEL pHM-SD formulation increasing by 6.61- and 5.37-fold, respectively. Collectively, the results from the current study showed that the inclusion of a hydrophilic polymer, pH modulator, and the amorphization of crystalline drugs in solid dispersion prepared by HME can be an effective strategy to improve the solubility and bioavailability of hydrophobic drugs without compromising the drug's physical stability.
ABSTRACT
OBJECTIVES: To investigate the effects of formulation composition on the physico-chemical and drug release properties of mucoadhesive buccal films prepared by melt extrusion technology, using a response surface methodology. METHODS: Salbutamol sulphate, an antiasthmatic drug was used for this study. Klucel hydroxypropylcellulose (HPC) EF (film-forming polymer), Benecel hydroxypropylmethylcellulose (HPMC) K-15M (drug release retardant) and polyethylene glycol (PEG) 4500 (plasticiser) were the three independent factors utilised for the study. The responses were fitted to a full quadratic model and P-values for each of the factors were used to determine their significance on the film characteristics. KEY FINDINGS: Films were successfully extruded using the corotating twin-screw extruder. The torque during extrusion was found to be significantly affected by all the three factors and no interaction between factors was observed. A significant interaction was observed between HPC and PEG 4500 for stiffness of films. For disintegration time and swelling index, a significant interaction was found between HPC and HPMC. The in vitro % drug release was directly correlated with HPMC content and not with other factors and varied from 69-89% at 4 h. CONCLUSIONS: The influence of extrusion process and formulation parameters on salbutamol sulphate films was elucidated, indicating the use of melt extrusion as a feasible method for film preparation.
Subject(s)
Adhesives/administration & dosage , Adhesives/chemistry , Mouth Mucosa/drug effects , Administration, Buccal , Albuterol/administration & dosage , Albuterol/chemistry , Anti-Asthmatic Agents/administration & dosage , Anti-Asthmatic Agents/chemistry , Cellulose/analogs & derivatives , Cellulose/chemistry , Chemistry, Pharmaceutical/methods , Drug Delivery Systems/methods , Drug Liberation/drug effects , Hot Temperature , Hypromellose Derivatives/chemistry , Plasticizers/chemistry , Polyethylene Glycols/chemistry , Polymers/chemistry , Technology, Pharmaceutical/methods , Tensile Strength/drug effectsABSTRACT
Over the last few decades, hot melt extrusion (HME) has emerged as a successful technology for a broad spectrum of applications in the pharmaceutical industry. As indicated by multiple publications and patents, HME is mainly used for the enhancement of solubility and bioavailability of poorly soluble drugs. This review is focused on the recent reports on the solubility enhancement via HME and provides an update for the manufacturing/scaling up aspects of melt extrusion. In addition, drug characterization methods and dissolution studies are discussed. The application of process analytical technology (PAT) tools and use of HME as a continuous manufacturing process may shorten the drug development process; as a result, the latter is becoming the most widely utilized technique in the pharmaceutical industry. The advantages, disadvantages, and practical applications of various PAT tools such as near and mid-infrared, ultraviolet/visible, fluorescence, and Raman spectroscopies are summarized, and the characteristics of other techniques are briefly discussed. Overall, this review also provides an outline for the currently marketed products and analyzes the strengths, weaknesses, opportunities and threats of HME application in the pharmaceutical industry.
Subject(s)
Drug Delivery Systems/methods , Pharmaceutical Preparations/chemistry , Technology, Pharmaceutical/methods , Equipment Design , Pharmaceutical Preparations/administration & dosage , Solubility , Technology, Pharmaceutical/instrumentationABSTRACT
The main aim of this study was to investigate the feasibility of preparing nanostructured lipid carrier (NLC) utilizing hot-melt extrusion (HME) coupled with probe sonication. The process parameters for HME and sonication were optimized and a modified screw configuration was used for extrusion. Lidocaine-loaded NLCs were successfully prepared by the proposed method with particle size <50 nm and polydispersity index <0.3. Transmission electron microscopy revealed the spherical nature of the particles. The second objective was to develop NLCs for topical controlled delivery of drug for pain management in cutaneous wounds. The entrapment efficiency of drug-loaded NLCs was found to be 73.9%. The formulation was subjected to permeation studies across porcine epidermis using a Franz diffusion setup. The drug permeation from the NLC-loaded carbopol gel was found to be sustained as compared to permeation from the gel without lipids. Furthermore, mechanistic studies were performed using tape stripped and intact skin models to ascertain the fact that the predominant rate controlling process was release of drug from the NLCs. In summary, the conventional HME process can be modified for continuous manufacturing of NLCs, which are otherwise prepared by batch processing involving multiple and complicated processing steps.
Subject(s)
Chemistry, Pharmaceutical/methods , Drug Carriers/chemical synthesis , Lipids/chemical synthesis , Nanostructures/chemistry , Skin Absorption , Animals , Drug Carriers/administration & dosage , Drug Carriers/metabolism , Drug Compounding , Lipids/administration & dosage , Nanostructures/administration & dosage , Organ Culture Techniques , Skin Absorption/drug effects , Skin Absorption/physiology , SwineABSTRACT
Ointments are generally prepared either by fusion or by levigation methods. The current study proposes the use of hot-melt extrusion (HME) processing for the preparation of a polyethylene glycol base ointment. Lidocaine was used as a model drug. A modified screw design was used in this process, and parameters such as feeding rate, barrel temperature, and screw speed were optimized to obtain a uniform product. The product characteristics were compared with an ointment of similar composition prepared by conventional fusion method. The rheological properties, drug release profile, and texture characteristics of the hot-melt extruded product were similar to the conventionally prepared product. This study demonstrates a novel application of the hot-melt extrusion process in the manufacturing of topical semi-solids.
