Design and Evaluation of Bioadhesive in-Situ Nasal Gel of Ketorolac Tromethamine

Abstract

Aqueous polymer solutions that are transformed into gels by changes in environmental conditions, such as temperature and pH, thus resulting in in-situ hydrogel formation, have recently attracted the attention of many investigators for practical biomedical or pharmaceutical applications.1-3) Ketorolac tromethamine (KT) is a potent non-narcotic analgesic with moderate anti-inflammatory activity and clinical studies indicate that it has a single dose efficacy, greater than morphine for postoperative pain and has excellent applicability in the emergency treatment of pain (break through cancer pain) and in the treatment of migraine headache. However, this drug is not currently available as nasal formulation. With intranasal delivery, a drug is absorbed directly into the systemic circulation, bypassing the problems that occur with oral administration, including fast onset of therapeutic effect without the discomfort and inconvenience of an injection.Pectin is a plant-derived polysaccharide commonly used in foods and drugs. Solutions containing drug plus pectin can be stored as liquids, and form gels when applied to the nasal mucosa.4) Chitosan is a linear polysaccharide derived from crustacean shells and is currently being investigated for many pharmaceutical applications because of its biocompatibility and biodegradability characteristics. 5) These observations made an impetus to prepare and evaluate chitosan and pectin based gelling systems of KT. ExperimentalMaterials KT, chitosan (purified, viscosity grade 50) and pectin were gift samples from Ranbaxy (India), CIFT (India) and India Citrus Products Ltd. (India), respectively. Hydroxypropyl methylcellulose (HPMC K15) (Sigma-Aldrich India Ltd., India), glacial acetic acid (S.D. Fine Chem., India), hydrochloric acid (Qualigens Fine Chem., India), dihydrogen potassium orthophosphate (Glaxo, India) and sodium hydroxide (E. Merck, India) were purchased. Double distilled water was used. All other chemicals used were of analytical reagent grade. Dialysis membrane (Sigma-Aldrich), Digital pH meter (Toshniwal Pvt. Ltd., India) and Brook Field viscometer (Tokimec Co., Japan) were also used.Methods For preparation of pectin or chitosan based gelling systems (Table 1); drug was mixed with polymer solution prepared in distilled water or 0.1 M glacial acetic acid, respectively and pH was adjusted to 4. For the preparation of HPMC K15 incorporated gels, HPMC K15 was also added while preparing pectin/chitosan solution and rest of the procedures were the same.The pH, angular viscosity and drug content of the prepared gels were studied using digital pH meter, Brookfield viscometer and UV-VIS spectrophotometer (JASCO 7800, Tokyo) at 322 nm, respectively.Gelation Studies Gelation studies were carried out by following a reported method 6) in different pH buffers (pH 5.0, 6.0, 6.6, 7.4) and were assessed by visual examination.Gelation temperature and gel melting was assessed by a modified procedure 7) as follows: 2 ml aliquot of gel was transferred to test tubes, sealed with aluminium f...

The effect of different storage temperatures on the physical properties of pectin solutions and gels

“…It has been shown [27] that small decreases in viscosity do not significantly change the drug release rates from pectin gels in vitro; this agrees with work in our group [28] which indicates that a change in viscosity from 5 to 2 mPas will have no significant effect on the drug release from pectin gels. This is summarised in Figure 4 where we can see that the times required to release 10%, 50% and 90% of a model drug (paracetamol) remain essentially constant with decreasing viscosity.…”

Development of the Composition of the Biopolymer Base for Nasal Gel

“…For intranasal delivery systems, an indicator of bioadhesion is important, since the duration of exposure on the mucosa determines therapeutic efficacy and depends on the rate of flow of the dosage form [9]. According to the data, if the adhesion exceeds 20 Newtons, then this polymer has acceptable mucoadhesive properties [10].…”

“…Adsorption activity was determined (spectrophotometrically on a Leki Instruments SS 1207 instrument (Finland) by the ability of a gel sample to adsorb methylene blue [7]. Bioadhesion was determined by separation and in vitro flow methods on a mucosa model consisting of a spunbond membrane (SPANLAB, Russia) treated with a 4 % aqueous solution of porcine stomach mucin type II (SIGMA, Sigma-Aldrich, USA, M 2378) [8,9]. Thermal stability of samples that were sterilized in sealed glass ampoules by dry steam in a BINDER-FD 115 autoclave for 8 minutes at 120 °C was evaluated by the percentage of delamination of the sterilized sample after centrifugation for 5 min at 3000 rpm on a Biosan LMC-3000 centrifuge (Latvia).…”

Hydroxypropylmethylcellulose films for prolonged delivery of the antipsychotic drug chlorpromazine

“…HPMC added to the mixtures employed for film preparation induced the formation of a gel with a particular viscosity as a function of its molecular weight. After drying, the more viscous mixtures produced a more packed network in which drug diffusion can be limited [23] …”