Showing papers on "Targeted drug delivery published in 1993"

Therapeutic drug delivery systems

Abstract: Therapeutic drug delivery systems comprising gas-filled microspheres comprising a therapeutic are described. Methods for employing such microspheres in therapeutic drug delivery applications are also provided. Drug delivery systems comprising gas-filled liposomes having encapsulated therein a drug are preferred. Methods of and apparatus for preparing such liposomes and methods for employing such liposomes in drug delivery applications are also disclosed.

Antibody-targeted Delivery of Doxorubicin Entrapped in Sterically Stabilized Liposomes Can Eradicate Lung Cancer in Mice

Abstract: Cancer chemotherapy is limited by adverse side effects resulting from toxicities to normal tissues. Targeted delivery of drugs to diseased tissues in vivo would help to reduce these side effects. Liposomes containing lipid derivatives of polyethylene glycol have circulation times sufficiently long to allow for effective in vivo drug delivery. Polyethylene glycol liposomes, containing entrapped doxorubicin, targeted to KLN-205 squamous cell carcinoma of the lung by means of specific antibodies attached at the liposome surface were capable of reducing tumor burden to a high degree and eradicating tumor in a significant percentage of mice.

Site-specific drug delivery to pilosebaceous structures using polymeric microspheres

Abstract: In order to improve the therapeutic index of adapalene, a new drug under development for the treatment of acne, site-specific delivery to the hair follicles using 50:50 poly(DL-lactic-co-glycolic acid) microspheres as particulate carriers was investigated in vitro and in vivo. The percutaneous penetration pathway of the microspheres was shown to be dependent on their mean diameter. Thus, after topical application onto hairless rat or human skin, adapalene-loaded microspheres (5-µm diameter) were specifically targeted to the follicular ducts and did not penetrate via the stratum corneum. The in vitro release of adapalene from the microspheres into artificial sebum at 37°C was controlled and faster than the in vivo sebum excretion in humans. Aiming to reduce either the applied dose of drug or the frequency of administration, different formulations of adapalene-loaded microspheres were evaluated in vivo in the rhino mouse model. A dose-related comedolytic activity of topical formulations of adapalene-loaded microspheres was observed in this model. Furthermore, by applying a site-specific drug delivery system (0.1% adapalene) every other day or by administering a 10-fold less concentrated targeted formulation (0.01%) every day, a pharmacological activity equivalent to a daily application of an aqueous gel containing drug crystals (0.1% adapalene) was observed. Since an aqueous gel containing 10% adapalene-loaded microspheres was not irritating in a rabbit skin irritancy test, this formulation was applied onto forearms of human volunteers. Site-specific drug delivery was further evidenced by follicular biopsy. These results support the view that follicular drug targeting using 5-µm polymeric microspheres may represent a promising therapeutic approach for the treatment of pathologies associated with pilosebaceous units.

Covalent polar lipid-peptide conjugates for use in salves

Abstract: This invention herein describes a method of facilitating the entry of drugs into cells at pharmokinetically useful levels and also a method of targeting drugs to specific organelles within the cell. This lipid/drug conjugate targeting invention embodies an advance over other drug targeting methods because through this method, intracellular drug concentrations may reach levels which are orders of magnitude higher than those achieved otherwise. Furthermore, it refines the drug delivery process by allowing therapeutic agents to be directed to certain intracellular structures. This technology is appropriate for use with antiproliferative drugs, in particular in combination with a multiplicity of other emolients and agents to make up topically-active substances such as salves, for rapid and efficient introduction of antiproliferative agents through the epidermis for treatment of skin diseases such as psoriasis.

Review: recent advances in lipid microsphere technology for targeting prostaglandin delivery.

Abstract: Although prostaglandin E1 (PGE1) and prostacyclin (PGI2) exhibit pharmacological activities in free form, it has been hypothesized and experimentally verified that carrier preparations can target them more effectively at lower doses, thus causing fewer side effects. Lipid microspheres (LM) with a diameter of 0.2 micron are drug carriers prepared from soybean oil and lecithin, and the drug is incorporated within the LM. Lipo-PGE1 and lipo-PGI2 are LM preparations of PGE1 and a PGI2 derivative that are designed to accumulate at the vascular lesions. The authors have achieved remarkable clinical effects against neuropathy and ulcers, severe hepatitis, congenital heart diseases, and acute cerebral thrombosis using these preparations. In this review, clinical observations, some basic studies including targeting delivery of lipo-PGE1 to the liver, and future indications for these preparations are introduced. Development of a new lipo-PGE1 (lipo-AS013) that overcomes the disadvantages of the preparation currently available is also discussed. Lipo-AS013, a prodrug of PGE1, is considered superior to free PGE1 in terms of its chemical stability in LM and the retention ratio of the drug in LM in the body.

Low molecular weight proteins as carriers for renal drug targeting: naproxen coupled to lysozyme via the spacer L-lactic acid.

Abstract: Low molecular weight proteins (LMWPs) are potential carriers for targeting drugs to the kidney. To test whether ester bonds are suitable for the reversible drug conjugation, the antiinflammatory drug naproxen (Nap) was conjugated to the LMWP lysozyme (LYSO) via an ester bond using an L-lactic acid spacer (Nap-lact-LYSO, 1:1:1). The distribution and degradation of the conjugate in rats were compared to those of an equimolar mixture of free drug and LMWP and of a directly coupled conjugate without spacer (Nap-LYSO). The plasma clearance of Nap-lact-LYSO closely resembled that of Nap-LYSO and LYSO itself. Its major accumulation site appeared to be the kidney as demonstrated by extracorporal -γ-camera counting of the LMWP. Renally released naproxen was excreted in the urine as 6-desmethyl-naproxen-sulfate (6-DMN-S). Apparently the kidneys represent the main sites of demethylation and sulfation after administration of the LMWP-coupled drug. In addition, the renal excretion of naproxen (including its metabolites) was significantly delayed and sustained as compared to that after injection of uncoupled naproxen. Using the L-lactic acid spacer LMWP conjugation, the renal selectivity of Nap was increased 5.6 ± 0.41-fold. Additional in vitro studies with Nap-lact-LYSO revealed that renal generation of the parent drug coincided with formation of low molecular weight catabolites, mainly as naproxen-L-lactic acid-lysine (Nap-lact-Lys). This indicated that in vitro the rate of cleavage of the ester bond is significantly slower than digestion of the carrier backbone itself. It is concluded that for drugs with free carboxyl groups the coupling to LMWPs via α-hydroxy acids can result in renal-specific delivery and endorenal drug release.

Iontophorett drug delivery

Abstract: Improved methods of ionophoretic drug delivery are described. By the intentional selection of drug(s) with specific characteristics, of ionotophoresis device, components or both permits the efficiency of drug delivery is increased.

Antibodies for treating and preventing disease: the potential role of polymeric controlled release.

Abstract: Following the identification of antibodies (Abs) as agents of immunity, it was hypothesized that individuals could be both (1) protected against disease by the transfer of unmodified Ab (passive immunization), and (2) cured of established disease by Ab armed with cytotoxic agents (immunotherapy). The development of monoclonal antibody (mAb) technology in 1975 reinvigorated these ideas. Although passive immunization has been practiced with great success for many years, successful tissue targeting by systemically delivered immunotoxins in humans has been documented in only a few cases. New modes of drug delivery, engineered for mAb-based products, may enable new applications of passive immunization and may provide improved tissue targeting for immunotherapy. By allowing sustained and tissue-localized delivery of mAb-conjugates, controlled-release polymers may play an important role in this effort. This article reviews the use of mAb in treating and preventing human disease, as well as the pharmacokinetics of Ab delivery. Two areas where controlled Ab release may yield new therapies are highlighted: sustained passive immunization of the mucus secretions and immunotherapy of brain tumors.

Lipophilic peptide-based carriers for targeted drug delivery using rational drug-binding design.

Abstract: Composition, methods of synthesis and uses of a peptide-based moiety for oral drug delivery, having the general formula: [X-A]2$(1,2)$ - [B]2$(1,2)$-1 - C, wherein X is an amino acid blocking group; A is selected from the group consisting of at least one amino acid; B is selected from the group consisting of lysine, ornithine and combinations thereof; C is selected from the group consisting of a free carboxyl group, or a protected carboxamide (CONH2); and n is the number of cycles of addition of B, including the addition of various xenobiotics and endogenous drugs.

A comparative study of the anticancer efficacy of doxorubicin carrying microspheres and liposomes using a rat liver tumour model.

Abstract: Due to low efficacy of chemotherapy in the treatment of liver cancer, several methods of drug targeting have been investigated. Liposomes designed to carry cytotoxic drugs to the liver are currently under clinical evaluation. While experimental evidence shows promise, this method of drug delivery has several disadvantages that include short shelf life and poor drug delivery into tumour tissue. An alternative strategy for targeted drug delivery involving use of ion exchange microspheres may overcome these limitations while still reducing systemic toxicity and maintaining therapeutic efficacy. The purpose of this study was to determine the relative antitumour efficacy of these two drugs carrying systems in the treatment of liver cancer. Compared to controls, DOX treatment with free drug, liposomes or microspheres significantly reduced tumour growth by 56% (P < 0.001), 51% (P < 0.01) and 79% (P < 0.001) respectively. Furthermore, the DOX-microsphere treatment was significantly better than either of the other DOX treatments (53%, P < 0.05) or the sham-microsphere treated group (64%, P < 0.05). Thus, drug microspheres can increase the anti-tumour efficacy compared to either free or liposomal drug while simultaneously reducing systemic toxicity.

Sugar-coated liposomes: a novel delivery system for increased drug efficacy and reduced drug toxicity.

Abstract: The uptake of glycoside-bearing liposomes by macrophages has been studied in vitro. Since the uptake was found to be specific for the end sugar attached to the glycoside, the possibility is raised that glycoside-bearing liposomes might be used in vivo as systems to deliver drugs to macrophages. Using the antileishmanial drug urea stibamine, these delivery systems have been tested in vivo against model leishmaniasis. The results indicate that the drug encapsulated in sugar-coated liposomes is much more potent in comparison with normal liposome-encapsulated drug or to the free drug. Mannose-grafted liposomes are more efficient in transportation of drugs compared with those bearing glucose. Toxicity studies involving blood parameters, histological staining of tissues and specific enzyme activities related to liver function, show no apparent toxicity with the drugs. Hence, drug encapsulated sugar-coated liposomes may have possible applications to humans.

Liposomes, a tale of drug targeting.

Abstract: (1993). Editorial: Liposomes, A Tale of Drug Targeting. Journal of Drug Targeting: Vol. 1, No. 1, pp. 3-6.

Perspectives in bioconjugate chemistry

Abstract: Introduction to bioconjugate chemistry. Part 1 Proteins: chemical modifications of proteins - history and applications radiohalogenation of proteins - a overview of radionuclides, labeling methods and reagents for conjugate labeling a brief survey of methods for preparing protein conjugates with dyes, haptens and cross-linking reagents. Part 2 Nucleic acids: a brief guide to nucleic acid chemistry conjugates of oligonucleotides and modified oligonucleotides - a review of their synthesis and properties sequence-selective DNA recognition by synthetic ligands DNA recognition by intercalator-minor-groove binder hybrid molecules. Part 3 Synthetic polymers: conjugates of anticancer agents and polymers - advantages of macromolecular therapeutics in vivo. Part 4 Targeted antibodies: recent advances with monoclonal antibody drug targeting for the treatment of human cancer the linkage of cytoxic drugs to monolonal antibodies for the treatment of cancer radiolabeling of monoclonal antibodies and fragments with technetium and rhenium. Part 5 Antibody-enzyme conjugates: enhancements of the thrombolytic potency of plasminogen activators by conjugation with clot-specific monoclonal antibodies conjugation of plasminogen activators and fibrin-specific antibodies to improve thrombolytic therapeutic agents purifying antibody-plasminogen activator conjugates generation of cytotoxic agents by targeted enzymes.

Intramuscular and subcutaneous drug delivery : encapsulation in liposomes and other methods to manipulate drug availability

Abstract: Introduction The intramuscular and subcutaneous routes of administration of drugs are often used when systemic effects are required and other routes (e.g., oral administration) cannot be used. Injection of a drug at an extravascular site leads to the initiation of a number of events that collectively make up the absorption process. A large number of variables are known to affect drug release after injection. Some tend to enhance drug absorption whereas others have the opposite effect. Examples of such parameters are molecular size or particle size (in the case of injectable suspensions), drug pKa value, pH of the formulation to be injected, solubility in water of the drug to be administered, drug solubility in tissue fluids and in vehiculum, viscosity of the formulation, initial drug concentration, age, gender, health, body movement, blood supply at the injection site, injection volume, injection technique and the site of injection, to mention a few.

Studies on the tissue distribution of liposome-associated clofazimine, an antileprosy drug.

Abstract: Clofazimine, a potent antimycobacterial drug, being highly lipophilic accumulates in fatty tissue and in the reticuloendothelial system causing dose-dependent side effects. In this study, the distribution of the free drug and liposome-associated drug was compared after intravenous administration in mice. Differences in the distribution of the drug were observed in the liver, spleen, kidney and lung tissues when injected as free drug and as liposome-associated drug. Following intravenous challenge with the free drug, the drug accumulated quickly and high concentrations of the drug were seen in the spleen, liver, kidney and lung even after 24 h, indicating poor clearance. However, with liposome-associated drug, increased levels were seen in liver, spleen and lung at 1 h with levels falling considerably at 24 h, with no accumulation in the kidney either at 1 h or 24 h after challenge. Clofazimine associated with neutral liposomes was preferentially targetted to spleen and lung, positively charged liposome-associated drug accumulated more in the lungs than in other tissues, while negatively charged liposome-associated drug was directed to liver and spleen. The results suggest that inclusion of clofazimine into liposome not only targets the drug to the organs concerned but also facilitates clearance of the drug, resulting in little accumulation. Also, renal accumulation is much lower as compared to the free drug. This suggests the potential usefulness of liposome as a carrier for clofazimine, thereby reducing the harmful side effects due to excessive accumulation of the drug.