C. Rostron

The influence of substitution type on the performance of methylcellulose and hydroxypropylmethycellulose in gels and matrices

Abstract The characteristics of matrices containing hydroxypropylmethylcellulose (HPMC) grades E4M, F4M or K4M, or methylcellulose A4M have been compared using thermomechanical analysis, differential scanning calorimetry (DSC), laser analysis, cloud points and via the dissolution of a model drug, propranolol hydrochloride, from matrices containing the cellulose ethers and prepared by direct compression. Dissolution rates of propranolol varied according to the drug/cellulose ether ratio within the matrix. Propranolol release from methylcellulose matrices was least affected by this ratio but the performance differences of the three grades of HPMC could not be distinguished. In the absence of drug, matrices containing methylcellulose disintegrated at 37 and 44°C. Water uptakes, as measured by DSC and gel layer thicknesses, were similar for each grade of cellulose ether. Matrices containing HPMC K4M tended to swell to the greatest extent. For all grades, swelling was greater in the axial rather than radial direction. Cloud points provided the best prediction of matrix performance.

The influence of the particle size of hydroxypropylmethylcellulose K15M on its hydration and performance in matrix tablets

Abstract The dissolution rate of propranolol hydrochloride from matrices containing different sized fractions of hydroxypropylmethylcellulose K15M has been examined. Generally, the release rate decreased as the particle size of hydroxypropylmethylcellulose was reduced from > 355 μM to 150–210 μM. Further reduction in size caused no further decrease in dissolution rate. Burst release of propranolol occurred at the extremes of large particle size and low matrix contents of hydroxypropylmethylcellulose K15M. Measurements of surface area by nitrogen adsorption indicated that all the sieve fractions of hydroxypropylmethylcellulose were poorly porous. Water uptake studies, measured by differential scanning calorimetry, suggested that initially the larger sized fraction of hydroxypropylmethylcellulose imbibed water faster than the smaller sized fraction.

The influence of drugs on the properties of gels and swelling characteristics of matrices containing methylcellulose or hydroxypropylmethylcellulose

Abstract The cloud points, matrix swelling and gel layer formation in matrices containing cellulose ethers and indomethacin, propranolol hydrochloride or tetracycline hydrochloride have been investigated. The two hydrochloride salts contributed to the matrix swelling and gel layer formation, maintaining the integrity of matrices containing methylcellulose. Gel layer formation, measured by thermomechanical analysis was most rapid, and the layer thickest, in matrices containing propranolol hydrochloride. This mimicked cloud point determination where propranolol salted the cellulose ethers into solution to a greater extent than tetracycline. The poorly soluble indomethacin failed to contribute to swelling and gel layer formation. Studies, using U-tube viscometry, indicated that the viscosity of gels containing HPMC E4M, HPMC F4M, HPMC K4M and methylcellulose reduced on storage. This appeared to be further catalysed by the inclusion of drugs, and especially of tetracycline hydrochloride in the gels.

The influence of concentration on the release of drugs from gels and matrices containing Methocel

The release of propranolol hydrochloride from hydroxypropylmethylcellulose and methylcellulose matrices has been examined at constant cellulose ether contents. As the drug content decreased, the release rate of propranolol became disproportionately higher. HPMC K4M, HPMC F4M and HPMC E4M all performed similarly. However, with methylcellulose matrices, a burst release at low drug levels was apparently due to a failure of the matrix to maintain integrity. Explanations were sought on the basis of diffusional studies. Apparent diffusion coefficients were in the order of 3.1–3.8 × 10−6 cm2 s−1 for propranolol hydrochloride. Each of the four grades performed similarly. Using similar diffusional studies, but HPMC K15M as the polymer, an apparent diffusion coefficient of 3.6 × 10−6 cm2 s−1 was derived, indicating that the coefficient was independent of molecular weight. The coefficient was dependent on HPMC content decreasing from approx. 5.5 × 10−6 to 3 × 10−6 cm2 s−1 as the HPMC content was increased from 5 to 15% w/w. The diffusion coefficients of tetracycline hydrochloride were lower and conversion to the free base is postulated as the explanation of previously described anomolous release for this drug from matrix tablets. The tortuosity of the gels was independent of the included drug.

Release of propranolol hydrochloride from matrix tablets containing hydroxypropylmethylcellulose K4M and carbopol 974

Abstract The release of propranolol hydrochloride from matrices containing hydroxypropylmethylcellulose and carbopol has been examined at different ratios of the polymers. Similar dissolution rates were found from the data corresponding to 5–35% of total drug release from matrices containing the same weight of polymer, but a burst release occurred from formulations containing 1: > 3 HPMC/carbopol once 35% of the drug had dissolved. In order to explain these results, studies on cloud points, water distribution, hydration and viscosity were carried out. Mixtures of both polymers resulted in a decrease in the values of the cloud points. Increased quantities of free water in the gels were apparent, producing a reduction in viscosity. Hydration studies, determined by DSC, on carbopol gels and matrices indicated that two different types of water were present in the scans of melting process. Additionally, the amount of water imbibed for this polymer was lower than that by HPMC or 1:1 mixture of the polymers. The burst release, during dissolution, may be explained by the formation of a complex between propranolol and carbopol.

Investigation of in-vitro release characteristics of NSAID-loaded polylactic acid microspheres

The intra-pulmonary delivery of non-steroidal anti-inflammatory drug-loaded PLA microspheres has potential utility in the treatment of inflammatory lung conditions such as asthma. Drug encapsulation efficiency and release kinetics depend upon a variety of parameters in the production process, all of which affect the properties of the microspheres produced. The release of piroxicam from PLA microspheres followed an apparently biphasic release profile. PLA microspheres containing indomethacin, however, exhibited kinetics which approached more closely to zero order release. The effect of microsphere production parameters upon these release profiles has been investigated. Results indicate that factors affecting the nature of the microsphere matrix have the greatest influence on release profiles. The use of halothane as organic solvent in the microsphere production increases the burst release effect. Residual halothane is known to be present in the microspheres, producing a less stable matrix, thus allowing much faster release of the drug. The nature of drug incorporated also appears to affect the nature of the microspheres matrix. Piroxicam-loaded microspheres possess a much more porous matrix than indomethacin-loaded microspheres, as evidenced by washing procedures. This difference could explain the difference in release profiles between the two types of microspheres.

Preparation and evaluation of microspheres prepared from novel polyester-ibuprofen conjugates blended with non-conjugated ibuprofen

A novel polyester, poly(glycerol-adipate-co-ω-pentadecalactone) (PGA-co-PL), was conjugated with a model drug, ibuprofen, through the free hydroxyl groups of the former and the free carboxyl group of the latter at various levels of substitution. The conjugated material was processed into microspheres by both emulsion solvent evaporation and spray-drying methods. Samples of conjugated material were also blended with non-conjugated drug and the microspheres produced were evaluated by various methods. Morphologically, the microspheres produced were satisfactory. However, there was some initial burst drug release from all samples, probably due to the presence of non-conjugated drug. Subsequent drug release was very slow due to the relative stability of the covalent bonding of the drug–polyester conjugate. Stability tests showed that storage at high relative humidity resulted in increased burst release.

Poly‐(d,l‐Lactic Acid) Microspheres Incorporating Histological Dyes for Intra‐pulmonary Histopathological Investigations

Polylactic acid (PLA) microspheres incorporating fluorescein as a histological marker have been prepared and used as a model for the testing of inhaled PLA microspheres (2–5 μm) in the lung. PLA microspheres (20 mg) were delivered to rabbits in the form of a saline nebulization.

Synthesis and Evaluation of Novel Polyester-Ibuprofen Conjugates for Modified Drug Release

Ibuprofen was conjugated at different levels to a novel polyester, poly(glycerol-adipate-co-ω-pentadecalactone) (PGA-co-PL), via an ester linkage to form a prodrug. The conjugates were characterized by differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), infrared (IR), gel permeation chromatography (GPC), ultraviolet (UV), and high-performance liquid chromatography (HPLC). The conjugates had a molecular weight between 18 and 24 kDa, and there was a suppression of the free hydroxyl groups within the conjugated polymer. DSC scans showed a lowering of the melting point (Tm) when compared with the polyester alone and a difference in the number and area of Tm peaks. Drug release studies showed an initial burst release (13–18%) followed thereafter by very slow release (maximum 35% after 18 days). Continuous work may produce ester-linked conjugates that are sufficiently labile to allow for complete release of ibuprofen over the time period studied.

Encapsulation and release of α-chymotrypsin from poly(glycerol adipate-co-ω-pentadecalactone) microparticles

Polymer-based microparticles are increasingly becoming of interest for a variety of applications including drug delivery. Recently poly(glycerol adipate) (PGA) and poly(glycol adipate-co-ω-pentadecalactone) have shown promise for delivery of dexamethasone phosphate and ibuprofen. In this paper the copolyester poly(glycol adipate-co-ω-pentadecalactone) was evaluated as a colloidal delivery system for encapsulated therapeutic proteins. Enzyme containing microparticles were prepared via the double water-in-oil-in-water (w/o/w) emulsion-solvent evaporation methodology. α-Chymotrypsin was used as a model proteolytic enzyme and its transfer was monitored during the emulsification process, in addition to in vitro release from formed particles. On average, 22.1 µg protein per 1 mg polymer was encapsulated, although gradual loss of activity of the protein, once released, was recorded. The work presented shows the potential of this polyester as a delivery system for enzymes via microparticles, with improvements to the system achievable via polymer and process optimization. The pendant hydroxyl groups on the polymer backbone provide future capacity for tailored alteration of the physical and chemical properties of the polymer, in addition to covalent attachment of various compounds.