No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Study of Metoprolol Tartrate delivery from biodegradable polymeric in situ implants for parenteral administration
Abstract
Two step surgery processes during administration and withdrawal of conventional implants and also the initial burst effect leading to poor drug loading have been considered as major complaints associated with in situ drug implants. The objective of this research was to develop in situ forming implant with highly water soluble drug Metoprolol Tartrate and biodegradable polymer DL-PLA to minimize these problems. Formulations were attempted to be developed with the incorporation of six different hydrophobic excipients namely, Arachis oil, Glyceryl monostearte, Stearic acid, Magnesium stearate, Cetostearyl alcohol and Stearyl alcohol. Effects of drug: polymer ratio and presence of hydrophobic excipients in formulations were observed on extent of drug burst, implant loading efficiency, duration of drug release and possible drug release mechanism. Loading efficiency of 5% theoretically drug loaded implant was found to be more than that with 10%. The lower drug loaded formulation more efficiently controlled the extent of drug burst while also extending the duration of drug release for a longer period of time. While addition of Arachis oil, Glycerol monostearte, Stearic acid, Magnesium stearate in 5% theoretically drug loaded formulations improved drug loading efficiency as compared to implants without excipients, Cetostearyl alcohol and Stearyl alcohol did not exert any such effects. Extent of burst was reduced as well as duration of drug release extended for Arachis oil, Glycerol monostearte and Stearic acid incorporated implants. Even though improved loading efficiency was observed with Magnesium stearate, an insignificant raise in burst and no change in duration of release were also observed. While with Cetostearyl alcohol and Stearyl alcohol the duration of release remained the same, the former increased the burst and the later reduced the same as compared to drug only implants. The release profile exhibited biphasic behavior in all the cases, an initial burst release phase followed by steady state drug release. The kinetics was evaluated for the both phases by fitting the data in four different kinetic models, namely, Zero order, First order, Higuchi and Korsmeyer-Peppas. While the burst phase fitted best with Zero order kinetics the steady-state phase complied more with Higuchi model.
... Where, LD is the amount of loaded drug in the implant and AD is the amount of added drug in the formulation [15]. ...
... It is also practically insoluble in water. Therefore, it probably decreases the dispersibility of the drug [15]. Cetyl Alcohol has been used in matrix-controlled drug delivery system for its hydrophobic property [24]. ...
Aim: Letrozole, a non-steroidal aromatase inhibitor, prevents the body from producing its own estrogen. The objective of the present study was to explore the fabrication and evaluation of natural biodegradable polymeric Letrozole implant for long term drug release targeting postmenopausal women with metastatic breast cancer. Methodology: The effect of different formulation variables i.e. different types of excipients and different hardening times (6 hrs, 12 hrs and 24 hrs) with exposure to formaldehyde vapour was investigated on drug loading efficiency and drug release profile. The result of in-vitro dissolution study was fitted to different kinetic models to evaluate the kinetic data. 2418 vitro Letrozole release from Gelatin-Sodium Alginate biodegradable polymeric implant was maximum, about 19 days, where Cetyl alcohol was incorporated as excipient. The release kinetics was explored and explained using Higuchi, zero and first order while the mechanism of release was confirmed with Korsmeyer-peppas model. Implants were found to follow Higuchi model the best in most cases. Good correlations were also obtained with Korsmeyere-Peppas model. According to these models, the drug released from implants were of diffusion controlled, where the drug was found to leave the matrix through pores and channels formed by entry of dissolution medium. Conclusion: The addition of different excipients and variation in hardening times were found to influence the drug loading efficiency and drug release significantly. Further investigation would confirm its potential in breast cancer therapy.
... Isradipine was completely dispersed in a polymer matrix, which enabled the material to be used as an oral drug delivery system [31]. A PLA-based implantation form with the hydrophilic β-blocker metoprolol was obtained in 2011 by Rahman et al. [45]. They used hydrophobic arachis oil and stearyl alcohol to improve the pharmacokinetic parameters of the drug. ...
... They used hydrophobic arachis oil and stearyl alcohol to improve the pharmacokinetic parameters of the drug. Each of the reagents caused a longer release time of the drug, up to 10 days [45]. Hong et al. described the addition of ancillary substances to prolong the release of the drug [30]. ...
Introduction: Arterial hypertension is a disease of civilization that requires long-term treatment. Recently, growing interest in natural and synthetic polymers as drug delivery vehicles in controlled release dosage forms for improving the efficacy of treatment has been observed.
Areas covered: This review introduces biodegradable synthetic polyesters as macromolecular carriers of antihypertensive drugs. Although various, synthetic and natural polymer-drug conjugates and/or polymeric carriers of anticancer drugs are currently under preclinical and clinical studies, there is no such data for antihypertensive drugs. Therefore, it seems appropriate to use such materials for the treatment of hypertension.
Expert opinion: There are currently only a few studies describing the use of synthetic polyesters in the arterial hypertension therapy. In order to the fact that there is a high demand for new, effective antihypertensive dosage forms, further studies for such drug carriers are certainly expected. Synthetic polyester carriers could improve the drug bioavailability and its pharmacokinetic properties by altering the pharmaceutical dosage form. This property is particularly useful for drugs with proven pharmacological action, but with limited application due to their inappropriate pharmacological properties. The development of new polymeric materials and technologies affords the opportunity to produce novel synthetic polyester DDSs.
Figure Graphical Abstract Gelatin-sodium alginate based levothyroxine sodium implant was prepared by heating and congealing methods. Implants were found to follow both the Higuchi and Korsmeyer-Peppas model of kinetics with variation in polymer ration. The drug release from the implants shows the combination of diffusion and erosion contributes to the control of drug release. Abstract The use of biodegradable polymers as drug carriers increases the drug entrapment efficiency and contributes to the sustained release action of the formulation. The purpose of this study was to prepare and evaluate a sustained release Gelatin-Sodium Alginate biodegradable polymeric implant containing Levothyroxine Sodium as a model drug. Heating and congealing methods were used for the preparation of implants in various ratios of Gelatin and Sodium Alginate (70:30, 80:20 and 90:10 % w/w). The prepared implants were exposed to formaldehyde for different time periods, (6hrs, 12hrs and 24hrs) for hardening. The formulated implants were evaluated for weight variation, thickness, presence of free formaldehyde, and in vitro release studies. The interactions between the drug and polymer, good surface integrity, and compatibility have been studied using SEM and DSC. The implant formulated with 80:20 % w/w Gelatin-Sodium Alginate ratio and hardened for 24 hours were found to produce the maximum sustained action for 30 days, and none of the implants contained formaldehyde. The effects of four different excipients with 80:20 ratio were also studied on drug loading efficiency and drug release profile. The drug loading efficiency and drug release were found to be significantly influenced by the addition of different excipients (Stearic Acid > GMS > PEG > Drug only > Cetyl) and variation in hardening times. The results of the in-vitro dissolution study were fitted to different kinetic models to evaluate the kinetic data. The kinetic release data were determined by finding the best fit of the release data to these models. Implants were found to follow both the Higuchi model and Korsmeyer-Peppas model of kinetics with the variation in polymer ratio. Therefore, drug release from the implants implies that a combination of diffusion and erosion contributes to the control of drug release.
Present investigation describes preparation of microspheres by solvent evaporation and W/O emulsion solvent evaporation methods followed by in vitro characterization of microspheres to evaluate the effect of method of preparation on physical properties and drug release profile of microspheres. The microspheres were found to be discrete, spherical with free flowing properties. The morphology (Scanning Electron Microscopy), particle size distribution, entrapment efficiency and their release profiles were investigated. The yield was found to be maximum in case of solvent evaporation method. The mean geometric particle size of microspheres prepared by solvent evaporation method was found in the ranges of 40-50 µm and the microspheres prepared by W/O emulsion solvent evaporation method was found in a ranges of 126-150 µm, respectively. The microcspheres formulation prepared by solvent evaporation method has shown greater encapsulation efficiency than W/O emulsion solvent evaporation method. The drug carrier interactions were investigated in solid state by Fourier Transform Infrared (FT-IR) spectroscopy study. In vitro drug release rate for microspheres was found to be sustained over 8 hours. Hence, it can be concluded that the formulation prepared by solvent evaporation method, has potential to deliver Losartan potassium in a controlled manner in a regular fashion over extended period of time in comparison to all other formulations and can be adopted for a successful oral delivery of Losartan potassium for safe management of hypertension. All data are verified as statistically significant by using one way ANOVA at 5 % level of significance (p < 0.05).
Poly(lactide) (PLA) has been developed and made commercially available in recent years. One of the major tasks to be taken before the widespread application of PLA is the fundamental understanding of its biodegradation mechanisms. This paper provides a short overview on the biodegradability and biodegradation of PLA. Emphasis is focused mainly on microbial and enzymatic degradation. Most of the PLA-degrading microorganisms phylogenetically belong to the family of Pseudonocardiaceae and related genera such as Amycolatopsis, Lentzea, Kibdelosporangium, Streptoalloteichus, and Saccharothrix. Several proteinous materials such as silk fibroin, elastin, gelatin, and some peptides and amino acids were found to stimulate the production of enzymes from PLA-degrading microorganisms. In addition to proteinase K from Tritirachium album, subtilisin, a microbial serine protease and some mammalian serine proteases such as alpha-chymotrypsin, trypsin, and elastase could also degrade PLA.
The objective of this work was to prepare and evaluate ketorolac tromethamine-loaded albumin microspheres using a factorial design. Albumin microspheres were prepared by emulsion cross-linking method. Selected formulations were characterized for their entrapment efficiency, particle size, surface morphology, and release behavior. Analysis of variance (ANOVA) for entrapment efficiency indicated that entrapment efficiency is best fitted to a response surface linear model. From the statistical analysis it was observed that as the drug:polymer (D:P) ratio and volume of glutaraldehyde increased, there was a significant increase in the encapsulation efficiency. Scanning electron microscopy of the microspheres revealed a spherical, nonporous and uniform appearance, with a smooth surface. Based on the entrapment efficiency and physical appearance, 9 formulations were selected for release study. The maximum particle size observed was below 40 microm. The release pattern was biphasic, characterized by an initial burst effect followed by a slow release. All selected microspheres, except those having less polymer proportion (D:P ratio is 1:1), exhibited a prolonged release for almost 24 hours. On comparing r (2) values for Higuchi and Peppas kinetic models, different batches of microspheres showed Fickian, non-Fickian, and diffusion kinetics. The release mechanism was regulated by D:P ratio and amount of cross-linking agent. From the experimental data obtained with respect to particle size and extent of drug release, it could be concluded that the prepared microspheres are useful for once-a-day intramuscular administration of ketorolac tromethamine.
Poly (lactide-co-glycolide) (PLG) is one of the most widely used biodegradable synthetic polymer for sustained release formulations. In the present work, in situ gel formulation has been developed using poly (lactide-co-glycolide) to deliver an antidiabetic drug-rosiglitazone, that can be given by subcutaneous route. The effect of different vehicles (N-methyl-2-pyrrolidone, triacetin), polymer concentration and comonomer ratios such as (65:35, 75:25, 85:15) in the polymer on the release of drug from the formulation were studied. The initial burst effect was substantially reduced when the PLG concentration was increased. Out of different comonomer ratios of PLG, the ratio 85:15 showed more sustained release with comparatively less burst effect. The formulations containing triacetin as the solvent showed controlled release of the drug with least burst effect. Good sustained and prolonged release of the drug coupled with biocompatibility characteristics make injectable in situ gel forming implant systems of PLG, a prospective implantable controlled release dosage form to deliver the drug in the therapy of diabetes.
Purpose: The aim of this paper was to develop a novel polymer-alloys technique for preparing controlled release microspheres of nomegestrol by using PLGA and PLCG, two kinds of polyester, as the combined matrix. Methods: Both in vitro and in vivo release characteristics of the obtained microspheres were demonstrated and the factors influencing the drug release pattern were discussed. In addition, the mechanism of the drug release was also investigated. Results: The results showed that nomegestrol released from the microspheres in a well-controlled pattern: low burst release on 1st day, shortened/eliminated lag time and drug released in a zero-order profile for 30 d. Conclusion: This method successfully overcame the drawbacks of traditional microencapsulation method in which the single kind of polyester was used as the matrix and uneven drug release profile was obtained.
Physico-chemical properties of an injectable polymeric implant system were evaluated and utilized to predict and understand the in vivo release of a model drug. The injectable implant system is based on the principle that a water insoluble polymer, dissolved in a biocompatible solvent, will precipitate upon contact with water. The solubility parameter of poly(dl-lactide) and dl-lactide-co-glycolide copolymers were experimentally determined by evaluating the solubility of these polymers in hydrogen bonding solvents having solubility parameters ranging from 8.9 to 14.8 (cal/cm3)12. The appropriate Flory-Huggins interaction parameters were then calculated at 25 and 37°C. Analysis of ternary phase diagrams indicated that the quantity of water needed to initiate precipitation, as well as the precipitation threshold, increased with increasing temperature in agreement with theoretical calculations. Rats were subcutaneously administered formulations comprised of polymer concentrations above and below the precipitation threshold, i.e., 40% w/w polymer. Formulations with polymer concentrations below the precipitation threshold exhibited approximately twice the initial release compared to formulations having a polymer content above the precipitation threshold. A key factor affecting the initial release of a model drug from formulations was the polymer content of the formulation with respect to the precipitation threshold. The reported method of analysis may be utilized to screen polymers and biocompatible solvents for use in these injectable implant systems.
The major challenge faced during the development of implantable dosage forms for site- specific delivery is monitoring the local concentration of the drug at or around the site of action. The tissue concentration at the site is generally measured by either sacrificing the animal at different points in time or by determining the amount of drug left in the implants at various time intervals. Unfortunately, there are no official in vitro dissolution methods available to study the release characteristics of drugs from this drug delivery system. The objective of this investigation was to develop a simple method using microdialysis sampling technique to serve as an in vitro dissolution method for implantable drug delivery systems. Ciprofloxacin implants were prepared by compressing ciprofloxacin microcapsules in poly(lactic acid) (PLA) and poly(lactic- glycolic acid) (PLGA). A sensitive HPLC method was developed and validated for the assay of Ciprofloxacin. An in vitro dissolution method was developed to study the release characteristics of drug from these implants. The method used a microdialysis sampling technique and a small sample volume of release medium. The various advantages and disadvantages of this method over other USP methods are discussed.
Some process variables of a liquid paraffin-in-water emulsion prepared with two nonionic surfactantts and cetostearyl alcohol were examined initially and following a forced aging process using particle size analysis and rheological techniques (continuous shear, creep and oscillation). The highest viscosities were obtained for emulsions made by adding the aqueous phase to the oil phase through an in-line homogeniser, homogenising at the highest speed or agitating at the lowest speed during cooling. The lowest viscosities were obtained for emulsions agitated to room temperature, cooled fastest or emulsified at the lowest possible emulsification temperature. On aging the consistency, of emulsions made by adding the oily phase to the aqueous phase or adding the surfactant with the lowest HLB value to the aqueous phase before emulsification, had deteriorated most, suggesting comparatively lower long term stability for emulsions made this way. The consistency of emulsions cooled at the slowest rate or agitated to room temperature deteriorated least suggesting comparatively better long term stability. The rheological properties of the emulsions were not related to variations in particle size distribution except when the homogenisation speed was increased but rather to the stabilities of viscoelastic networks formed in the continuous phase and around the oil droplets. The composition and extent to which these structures are formed during manufacture is likely to be largely responsible for the rheological properties and the stability of an emulsion, and this will be investigated further in a later paper.
Ibuprofen microspheres were prepared using an aqueous dispersion method. The method was adapted so that two processing factors, cooling time and stirring rate, could be altered. The subsequent effects of altering these parameters on the characterisation of the microspheres and the drug release kinetics were investigated. Particle size analysis showed that both stirring rate and cooling time significantly affected the mean particle size although the effects were independent of each other. In vitro release data were fitted to several models, the Higuchi square root of time model (with appropriate limits) giving the best fit for the release data. Increasing the cooling time or decreasing the stirring rate decreased the release of drug from the system. By using this method of manufacture, which allows alteration of processing parameters, it would be relatively straightforward to produce microspheres with tailored in vitro release characteristics.
Heptakis (2,3,6-tri-O-acetyl)-β-cyclodextrin) (TAβCyD) and octakis (2,3,6-tri-O-acetyl-γ- cyclodextrin) (TAβCyD) were prepared for use as hydrophobic carriers of buserelin acetate (BLA), an agonist of luteinizing hormone-releasing hormone. The results from this study suggest that the in vitro release of BLA from the peanut oil suspension into the aqueous phase was retarded by complexation with TACyDs. A single subcutaneous injection of the oily suspension of BLA containing TAβCyD and TAγCyD in rats led to retardation of plasma levels of BLA containing in 25- and 39-fold longer mean residence times, respectively, than that of BLA alone. Simultaneously with the suppression of plasma testosterone to castrate level, the pharmacological effectiveness of BLA continued for 1–2 weeks and significant weight reduction of genital organs was observed due to the antigonadal effect. Since TAβCyD and TAγCyD were degraded enzymatically in rat skin homogenates, both TACyDs can be useful as bioabsorbable sustained-release carriers for hydrophilic peptides following the subcutaneous injection of an oily suspension.
Spherical ibuprofen-cetostearyl alcohol matrices were prepared using a technique involving melting and suspension of drug-containing cetostearyl alcohol in an aqueous medium. The resulting emulsion was cooled under rapid stirring to produce the spheres. Release of ibuprofen from the pellets was modelled using standard drug-release equations. Numerical fits indicate that the contracting sphere model (the cube root equation) was the most appropriate one for describing the complete release profiles. Within the range of drug release rates of 20–80% the model was indistinguishable from the Higuchi square root of time model. Using the slopes from the latter model, the effects of drug loading, particle size and stirring speed during the preparation of the pellets were investigated. Differential scanning calorimetry was used to explain some unusual observations and it was shown that eutectic formation between ibuprofen and cetostearyl alcohol may account for the unusually high ibuprofen release rates from pellets containing ibuprofen, at levels close to the eutectic composition.
Biodegradable polymers are used in diffusion controlled, swelling controlled and chemically controlled delivery systems. In this study, PLGA copolymers were used in a formulation which forms a gel matrix immediately on contact with aqueous fluids. This property of the formulation can circumvent the need for making a surgical incision to implant the matrix. The gel matrix thus formed will release the drug slowly (over a period of weeks to months) and ultimately biodegrade depending on the composition of the polymer used. In vitro release studies using small molecules and macromolecules, such as proteins, indicate that the drug release is influenced by the concentration of the polymer, physico-chemical properties of the drug, method of incorporation of the drug in the formulation and the presence of other excipients. The drug release can therefore be modified to suit the desired release characteristics. This novel formulation design for a biodegradable injectable implant can provide prolonged release while avoiding the necessity for surgical procedures.
Abietic acid (85 per cent pure) was extracted from rosin N Grade and further standardized. Abietic acid derivatives were prepared by heating abietic acid with glycerol and intermediate reaction products with different acid values were collected. Salicylic acid granules were encapsulated using a 10 per cent solution of abietic acid and its derivatives by standard spray pan technique. The coated microcapsules were evaluated for moisture absorption, dissolution and flow properties. The result showed that abietic acid glycerol derivatives, AaG-54 and AaG-20 had better moisture protection properties. Dissolution studies indicate that these derivatives could be used for delayed release of drugs.
Slow-releasing paracetamol tablet formulations were produced and their in vitro dissolution profiles and in vivo absorption characteristics were determined and compared with a conventional rapidly-disintegrating commercial formulation. A correlation between saliva and plasma levels of the drug was confirmed and this allowed estimation of some simple pharmacokinetic parameters from the saliva paracetamol data. The in vitro data correlated with the in vivo parameters and this enabled the dissolution test results to be used in predictive manner in the development of a compression-coated slow release formulation which produced therapeutic levels of the drug for up to 5 h.
Although the significance of burst release in controlled delivery systems has not been entirely ignored, no successful theories have been put forth to fully describe the phenomenon. Despite the fact that the fast release of drug in a burst stage is utilized in certain drug administration strategies, the negative effects brought about by burst can be pharmacologically dangerous and economically inefficient. Therefore a thorough understanding of the burst effect in controlled release systems is undoubtedly necessary. In this article, we review experimental observations of burst release in monolithic polymer controlled drug delivery systems, theories of the physical mechanisms causing burst, some of the unique ideas used to prevent burst, and the treatment of burst release in controlled release models.
The ability to inject a drug incorporated into a polymer to a localized site and have the polymer form a semi-solid drug depot has a number of advantages. Among these advantages is ease of application and localized, prolonged drug delivery. For these reasons a large number of in situ setting polymeric delivery systems have been developed and investigated for use in delivering a wide variety of drugs. In this article we introduce the various strategies that have been used to prepare in situ setting systems, and outline their advantages and disadvantages as localized drug delivery systems.
Noradrenergic Transmission
- H P Rang
- M M Dale
- J M Ritter
- P K Moore
Rang HP, Dale MM, Ritter JM and Moore PK. Noradrenergic
Transmission. In: Abramson JH, Mandelstam J, Weber M and
Williams RJP, editors. Pharmacology, 5th ed. Elsevier Science
Limited, 2003. p. 180-181.
Study of steroidal drug delivery from biodegradable polymeric systems using in situ formation of implants for parenteral administration. Thesis (PhD)
- S Islam
Islam S. Study of steroidal drug delivery from biodegradable
polymeric systems using in situ formation of implants for
parenteral administration. Thesis (PhD). University of Dhaka;
2008. p. 80-113, 138-200.
Handbook of Pharmaceutical Excipients. London: Science and Practice
- C R Raymond
- J S Paul
- J W Paul
Raymond CR, Paul JS and Paul JW, editors. Handbook of
Pharmaceutical Excipients. London: Science and Practice; 2003.
The Science of Dosage Form Design
Aulton ME, editor. Pharmaceutics, The Science of Dosage Form
Design. New York: Churchill Livingstone; 2002.
Study of some sustained release granulation of aspirin
- C M Prasad
- G P Srivastava
Prasad CM and Srivastava GP. Study of some sustained release
granulation of aspirin. Indian J Hosp Pharm 1971; 8: 21-28.