Conventional forms of drug administration generally rely on pills, eye drops, ointments, and intravenous solutions. Recently, a number of novel drug delivery approaches have been developed. These approaches include drug modification by chemical means, drug entrapment in small vesicles that are injected into the bloodstream, and drug entrapment within pumps or polymeric materials that are placed in desired bodily compartments (for example, the eye or beneath the skin). These techniques have already led to delivery systems that improve human health, and continued research may revolutionize the way many drugs are delivered.

http://science.sciencemag.org/content/sci/249/4976/1527.full.pdf

New methods of drug delivery.

Biodegradation and biocompatibility of PLA and PLGA microspheres

Years of cumulative research can result in the development of a clinically useful drug, providing either a cure for a particular disease or symptomatic relief from a physiological disorder. A lead compound with a desired pharmacological activity may have associated with it undesirable side effects, characteristics that limit its bioavailability, or structural features which adversely influence its metabolism and excretion from the body. Bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents. The concept of bioisosterism is often considered to be qualitative and intuitive.1 The prevalence of the use of bioisosteric replacements in drug design need not be emphasized. This topic has been reviewed in previous years.2-5 The objective of this review is to provide an overview of bioisosteres that incorporates sufficient detail to enable the reader to understand the concepts being delineated. While a few popular examples of the successful use of bioisosteres have been included, the George Patani graduated with a B.Pharm. in 1992 from the College of Pharmaceutical Sciences, Mangalore University at Manipal, India. In 1996, he received his M.S. in Pharmaceutical Science at Rutgers University under the direction of Professor Edmond J. LaVoie. He is presently pursuing graduate studies in pharmaceutics. His current research interests are focused on drug design and controlled drug delivery.

https://www.mch.estranky.sk/file/228/1996chemrev96-3147-76_bioisosterism.pdf

Bioisosterism: A Rational Approach in Drug Design.

The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices.

This review covers recent developments in the area of particle engineering via spray drying. The last decade has seen a shift from empirical formulation efforts to an engineering approach based on a better understanding of particle formation in the spray drying process. Microparticles with nanoscale substructures can now be designed and their functionality has contributed significantly to stability and efficacy of the particulate dosage form. The review provides concepts and a theoretical framework for particle design calculations. It reviews experimental research into parameters that influence particle formation. A classification based on dimensionless numbers is presented that can be used to estimate how excipient properties in combination with process parameters influence the morphology of the engineered particles. A wide range of pharmaceutical application examples—low density particles, composite particles, microencapsulation, and glass stabilization—is discussed, with specific emphasis on the underlying particle formation mechanisms and design concepts.

/pdf/pharmaceutical-particle-engineering-via-spray-drying-1wv9pxpwlb.pdf

Pharmaceutical particle engineering via spray drying.

To screen a suitable polymer for preparing a controlled-release dosage form effective for one month, square plates of polyactic acid (PLA) with average molecular weights of 6000 to 50000 and copoly(lactic/glycolic) acid (PLGA) with average molecular weights of 6000 to 13500 and a copolymer ratio of 90/10 to 55/45 were implanted in rats subcutaneously, and the weight losses were determined over 100 d. Typically the pattern of weight loss was biphasic with a lag time followed by a period when the weight fell exponentially. The lag times and the half lives of the degradation period increased with increase in the molecular weight or with decrease in glycolide content. Release of leuprolide acetate from PLA microcapsules at the injection site in rats (in vivo release) tended to be comparable to the bioerosion rate of the polymer used as the wall substance, and the in vivo release of the drug from PLGA microcapsules tended to be comparable to the biodegradation rate of the polymer. The in vivo release profile of the drug from microcapsules prepared with PLGA of average molecular weight 14000 and copolymer ratio 75/25 was ideal for one month's controlled release. The in vivo release profile from microcapsules injected subsutaneously in rats was comparable to the in vitro release.

https://www.jstage.jst.go.jp/article/cpb1958/36/7/36_7_2576/_pdf

In Vivo Release Profiles of Leuprolide Acetate from Microcapsules Prepared with Polylactic Acids or Copoly(Lactic/Glycolic) Acids and in Vivo Degradation of These Polymers

The pharmacokinetic behaviour of leuprolide acetate from a controlled release parenteral dosage form has been studied in rats and dogs. The release of the drug in rats after a single subcutaneous injection exhibited pseudo-zero-order kinetics for one month in doses ranging from 0.0135 to 1.35 mg/rat; the release rate at a dose of 1.35 mg/rat was 2.8% of dose/day; after intramuscular injection the response was similar. In rats, the serum leuprolide acetate levels increased sharply immediately after injection by either route as a consequence of the initial release of the drug; subsequently, the levels attained a plateau for two weeks. The serum level profiles in dogs showed essentially the same pattern as those in rats. When the dosage form was injected into rats, the serum testosterone level (a pharmacological index) sharply peaked, abruptly decreased to below the normal level, and then was sustained at a suppressed level for over six weeks at a dose of 1.35 mg/rat (equivalent to 3 mg kg-1) and higher, while the serum testosterone level after an injection of 0.0135 and 0.135 mg/rat was not sufficiently suppressed. The profiles in dogs showed essentially the same pattern as those in rats. With multiple administrations (once every 4 weeks), serum testosterone levels in dogs did not show any sharp rise after the second and third injections. Changes in rat reproductive organ weights agreed well with the serum testosterone profile in the suppression. The results demonstrate that this dosage form releases the drug at a constant rate for one month and has a long-acting potency.

Controlled release of LHRH agonist, leuprolide acetate, from microcapsules: serum drug level profiles and pharmacological effects in animals.

Vaginal Absorption of a Potent Luteinizing Hormone-Releasing Hormone Analog (Leuprolide) in Rats I: Absorption by Various Routes and Absorption Enhancement

Leuprolide acetate is a highly potent analog of luteinizing hormone-releasing hormone. We have prepared 1-month release injectable microcapsules of leuprolide acetate using a biodegradable polymer, poly (dl-lactide-co-glycolide), to treat an endocrine-dependent tumor, prostate cancer. In the present study, the possibility using the microcapsules to treat endometriosis was investigated. In rats, the microcapsules exhibited a pseudo-zero order release from the injection site for 1 month after being administered s.c. and i.m., and maintained effective constant serum levels of the analog during the 4-week treatment. A single injection of the microcapsules (100 micrograms/kg/day as leuprolide acetate) suppressed luteinizing hormone, follicle-stimulating hormone and estradiol for more than 4 weeks, and caused a dramatic regression of growth of Jones experimental endometriosis model in female rats. These results encourage the belief that a 1-month release parenteral preparation of leuprolide acetate may be potentially useful in the therapy of endometriosis in human beings.

One-month release injectable microcapsules of a luteinizing hormone-releasing hormone agonist (leuprolide acetate) for treating experimental endometriosis in rats.

A method of producing sustained-release microcapsules containing a biologically active substance from an W/O emulsion comprising an inner aqueous phase containing said biologically active substance and an external oil phase containing a biodegradable polymer, characterized in that microcapsules formed on microencapsulation of said biologically active substance with said biodegradable polymer are heated at a temperature not lower than the glass transition temperature of said biodegradable polymer but not so high as to cause aggregation of the microcapsules. This method enables the production of very useful sustained release microcapsules adapted to release a bologically active substance at a calculated rate over a protracted time period starting immediately following administration without an initial burst within one day following administration.

Yasuaki Ogawa

Papers

In Vivo Release Profiles of Leuprolide Acetate from Microcapsules Prepared with Polylactic Acids or Copoly(Lactic/Glycolic) Acids and in Vivo Degradation of These Polymers

Controlled release of LHRH agonist, leuprolide acetate, from microcapsules: serum drug level profiles and pharmacological effects in animals.

Vaginal Absorption of a Potent Luteinizing Hormone-Releasing Hormone Analog (Leuprolide) in Rats I: Absorption by Various Routes and Absorption Enhancement

One-month release injectable microcapsules of a luteinizing hormone-releasing hormone agonist (leuprolide acetate) for treating experimental endometriosis in rats.

Method of producing sustained-release microcapsules