Gel s liposomski uklopljenim kloramfenikolom: karakterizacija i oslobađanje in vitro

The aim of our study was to develop a liposomal carrier system for the local treatment of bacterial vaginosis, capable to efficiently deliver entrapped drug during an extended period of time. Chloramphenicol was entrapped in liposomes composed of egg phosphatidylcholine/egg phosphatidylgycerol-sodium (9:1, molar ratio) and prepared by two different methods, the proliposome method and the polyol dilution method. Both liposome preparations were characterised and compared for particle size, polydispersity, entrapment efficiency and tested for in vitro stability in media that simulate human vaginal conditions (buffer pH 4.5 and vaginal fluid simulant). To achieve application viscosity of liposomes and to further improve their stability, liposomes prepared by the proliposome method were incorporated in the bioadhesive gel made of Carbopol 974P NF resin. In vitro release studies of liposomes incorporated in the gel have shown a prolonged release of entrapped chloramphenicol compared to control gel. Even after 24 hours of incubation in the vaginal fluid simulant, more than 40% of the originally entrapped drug was still retained in the gel. Storage stability studies have proven the ability of the Carbopol 974P NF gel to preserve the original size distribution of incorporated liposomes. All the performed experiments confirm the applicability of liposomes as a novel drug carrier system for the local treatment of bacterial vaginosis.Cilj ovog rada bio je priprava i razvoj liposomskog terapijskog sustava s uklopljenim kloramfenikolom namijenjenog lokalnoj terapiji bakterijskog vaginitisa. Kloramfenikol je uklopljen u liposome fosfolipidnog sustava fosfatidilkolin/fosfatidilglicerol (molarni omjer 9:1), priređene dvjema metodama, proliposomskom i metodom razrjeđenja poliola. Obje preparacije su uspoređene i liposomi su karakterizirani s obzirom na veličinu čestica, polidisperznost, te uspješnost uklapanja. Provedena su ispitivanja stabilnosti liposoma in vitro u medijima koji svojim pH i sastavom oponašaju humanu vaginalnu sluznicu (pufer pH 4.5 i umjetni vaginalni medij). Kako bi se postigla prikladna viskoznost pripravka i dodatno povećala stabilnost liposoma namijenjenih vaginalnoj primjeni, liposomi su umiješani u bioadhezivni gel pripravljen iz karbopola 974P NF. In vitro ispitivanja s liposomima uklopljenima u gel pokazala su produljeno oslobađanje uklopljenog kloramfenikola. Pritom se čak nakon 24 sata inkubacije u umjetnom vaginalnom mediju više od 40% početno uklopljenog kloramfenikola zadržalo u gelu. Ispitivanja stabilnosti liposoma u gelu tijekom skladištenja potvrdila su povoljan učinak gela na očuvanje početne raspodjele uklopljenih liposoma s obzirom na veličinu. Ispitivanja provedena u ovom radu potvrđuju mogućnost primjene liposoma kao novog terapijskog sustava u lokalnoj terapiji bakterijski vaginalnih infekcija

Gel s liposomski uklopljenim kloramfenikolom: karakterizacija i oslobađanje in vitro

The aim of our study was to develop a liposomal carrier system for the local treatment of bacterial vaginosis, capable to efficiently deliver entrapped drug during an extended period of time. Chloramphenicol was entrapped in liposomes composed of egg phosphatidylcholine/egg phosphatidylgycerol-sodium (9:1, molar ratio) and prepared by two different methods, the proliposome method and the polyol dilution method. Both liposome preparations were characterised and compared for particle size, polydispersity, entrapment efficiency and tested for in vitro stability in media that simulate human vaginal conditions (buffer pH 4.5 and vaginal fluid simulant). To achieve application viscosity of liposomes and to further improve their stability, liposomes prepared by the proliposome method were incorporated in the bioadhesive gel made of Carbopol 974P NF resin. In vitro release studies of liposomes incorporated in the gel have shown a prolonged release of entrapped chloramphenicol compared to control gel. Even after 24 hours of incubation in the vaginal fluid simulant, more than 40% of the originally entrapped drug was still retained in the gel. Storage stability studies have proven the ability of the Carbopol 974P NF gel to preserve the original size distribution of incorporated liposomes. All the performed experiments confirm the applicability of liposomes as a novel drug carrier system for the local treatment of bacterial vaginosis.Cilj ovog rada bio je priprava i razvoj liposomskog terapijskog sustava s uklopljenim kloramfenikolom namijenjenog lokalnoj terapiji bakterijskog vaginitisa. Kloramfenikol je uklopljen u liposome fosfolipidnog sustava fosfatidilkolin/fosfatidilglicerol (molarni omjer 9:1), priređene dvjema metodama, proliposomskom i metodom razrjeđenja poliola. Obje preparacije su uspoređene i liposomi su karakterizirani s obzirom na veličinu čestica, polidisperznost, te uspješnost uklapanja. Provedena su ispitivanja stabilnosti liposoma in vitro u medijima koji svojim pH i sastavom oponašaju humanu vaginalnu sluznicu (pufer pH 4.5 i umjetni vaginalni medij). Kako bi se postigla prikladna viskoznost pripravka i dodatno povećala stabilnost liposoma namijenjenih vaginalnoj primjeni, liposomi su umiješani u bioadhezivni gel pripravljen iz karbopola 974P NF. In vitro ispitivanja s liposomima uklopljenima u gel pokazala su produljeno oslobađanje uklopljenog kloramfenikola. Pritom se čak nakon 24 sata inkubacije u umjetnom vaginalnom mediju više od 40% početno uklopljenog kloramfenikola zadržalo u gelu. Ispitivanja stabilnosti liposoma u gelu tijekom skladištenja potvrdila su povoljan učinak gela na očuvanje početne raspodjele uklopljenih liposoma s obzirom na veličinu. Ispitivanja provedena u ovom radu potvrđuju mogućnost primjene liposoma kao novog terapijskog sustava u lokalnoj terapiji bakterijski vaginalnih infekcija

Dual Centrifugation - A Novel “in-vial” Liposome Processing Technique

Conventional liposome preparation methods bear many limitations, such as poor entrapment efficiencies for hydrophilic drugs, batch size limitations, and limited options for aseptic manufacturing. Liposome preparation by dual centrifugation (DC) is able to overcome most of these limitations. DC differs from normal centrifugation by an additional rotation of the samples during the centrifugation process. Thus, the direction of the centrifugal forces changes continuously in the sample vials. The consequential powerful sample movements inside the vials result in powerful homogenization of the sample. Since this “in-vial” homogenization is optimal for viscous samples, semisolid “vesicular phospholipid gels” (VPGs) are preferred intermediates in the liposome manufacturing by DC. The DC method easily enables aseptic preparation and is gentler as compared to other methods, such as high-pressure homogenization. The method allows very small samples to be prepared, and VPG batches down to 1–5 mg scale have been prepared successfully. VPGs have several applications; they are attractive as depot formulations, or as stable storage intermediates, and can be easily transferred into conventional liposomal formulations by simple dilution. Here, we aim to present the novel DC-liposome technique; the concept, advantages, and limitations; and provide an overview of the experiences of liposome preparation by DC so far

Liposomes-In-Hydrogel Delivery System Enhances the Potential of Resveratrol in Combating Vaginal Chlamydia Infection

Chlamydia trachomatis is the most common cause of bacterial sexually transmitted infections and causes serious reproductive tract complications among women. The limitations of existing oral antibiotics and treatment of antimicrobial resistance require alternative treatment options. We are proposing, for the first time, the natural polyphenol resveratrol (RES) in an advanced delivery system comprising liposomes incorporated in chitosan hydrogel, for the localized treatment of C. trachomatis infection. Both free RES and RES liposomes-in-hydrogel inhibited the propagation of C. trachomatis in a concentration-dependent manner, assessed by the commonly used in vitro model comprising McCoy cells. However, for lower concentrations, the anti-chlamydial effect of RES was enhanced when incorporated into a liposomes-in-hydrogel delivery system, with inhibition of 78% and 94% for 1.5 and 3 µg/mL RES, respectively for RES liposomes-in-hydrogel, compared to 43% and 72%, respectively, for free RES. Furthermore, RES liposomes-in-hydrogel exhibited strong anti-inflammatory activity in vitro, in a concentration-dependent inhibition of nitric oxide production in the LPS-induced macrophages (RAW 264.7). The combination of a natural substance exhibiting multi-targeted pharmacological properties, and a delivery system that provides enhanced activity as well as applicability for vaginal administration, could be a promising option for the localized treatment of C. trachomatis infection

Liposomes-In-Hydrogel Delivery System Enhances the Potential of Resveratrol in Combating Vaginal Chlamydia Infection

Chlamydia trachomatis is the most common cause of bacterial sexually transmitted infections and causes serious reproductive tract complications among women. The limitations of existing oral antibiotics and treatment of antimicrobial resistance require alternative treatment options. We are proposing, for the first time, the natural polyphenol resveratrol (RES) in an advanced delivery system comprising liposomes incorporated in chitosan hydrogel, for the localized treatment of C. trachomatis infection. Both free RES and RES liposomes-in-hydrogel inhibited the propagation of C. trachomatis in a concentration-dependent manner, assessed by the commonly used in vitro model comprising McCoy cells. However, for lower concentrations, the anti-chlamydial effect of RES was enhanced when incorporated into a liposomes-in-hydrogel delivery system, with inhibition of 78% and 94% for 1.5 and 3 µg/mL RES, respectively for RES liposomes-in-hydrogel, compared to 43% and 72%, respectively, for free RES. Furthermore, RES liposomes-in-hydrogel exhibited strong anti-inflammatory activity in vitro, in a concentration-dependent inhibition of nitric oxide production in the LPS-induced macrophages (RAW 264.7). The combination of a natural substance exhibiting multi-targeted pharmacological properties, and a delivery system that provides enhanced activity as well as applicability for vaginal administration, could be a promising option for the localized treatment of C. trachomatis infection

Stabilnost amlodipin besilata i atenolola u jednoslojnim i dvoslojnim tabletama

Multi-drug tablets of amlodipine besylate and atenolol were prepared as either mono-layer (mixed matrix) or bi-layer tablets containing each drug in a separate layer by using similar excipients and processing. Each tablet batch was packed in strip and blister packs and kept under accelerated temperature and humidity conditions. The stability of two tablet and packaging types was compared by HPLC analysis after 0, 1, 3 and 4.5 months and expressed as the content of intact amlodipine and atenolol. The content of atenolol did not decline regardless of tablet and packaging type. Amlodipine content in bi-layer tablets decreased to about 95 and 88% when packed in strips and blisters, respectively. When prepared as mono-layer tablets, the content decreased to 72 and 32%, respectively. The study revealed that the bi-layer tablet formulation was more stable than the mono-layer type. Further, the stability was increased when the tablets were packed in aluminium strips as compared to PVC blisters.Tablete s amlodipinom i atenololom pripremljene su ili u obliku jednoslojne tablete (miješani matriks) ili kao dvoslojne tablete (lijekovi u zasebnim slojevima) koristeći slične pomoćne tvari i uvjete tabletiranja. Tablete su pakirane u dvije vrste pakiranja, aluminijske folije (strip) ili PVC (blister) i čuvane u uvjetima ubrzanog starenja. Stabilnost je određivana pomoću HPLC metode nakon 0, 1, 2, 3 i 4,5 mjeseci i izražena kao sadržaj intaktnog lijeka. Sadržaj atenolola nije se značajno promijenio bez obzira na tip tablete ili pakiranje. Sadržaj amlodipina u dvoslojnim tabletama smanjio se na 95 % (tablete u strip pakiranju) i 88 % (tablete u blister pakiranju). Istodobno, u jednoslojnom tipu kombiniranih tableta sadržaj se smanjio na 72 % (strip pakiranje) i 32 % (blister pakiranje). Rezultati pokazuju da su dvoslojne tablete s amlodipinom i atenololom stabilnije od jednoslojnih. Štoviše, pakiranje tableta u aluminijsku foliju u obliku strip pakiranja povećava njihovu stabilnost u usporedbi s PVC pakirnim materijalom (blister)

Biologics: the role of delivery systems in improved therapy

The beginning of the 21st century saw numerous protein and peptide therapeuticals both on the market and entering the final stages of clinical studies. They represent a new category of biologically originated drugs termed biologics or biologicals. Their main advantages over conventional drugs can be summarized by their high selectivity and potent therapeutic efficacy coupled with limited side effects. In addition, they exhibit more predictable behavior under in vivo conditions. However, up to now most of the formulations of biologics are designed and destined for the parenteral route of administration. As a consequence, many suffer from short plasma half-lives, resulting in their frequent administration and ultimately poor patient compliance. This review represents an attempt to address some of the challenges and promises in the product development of biologics both for parenteral and noninvasive administration. Some of the products currently in the pipeline of pharmaceutical development and corresponding perspectives are discussed in more detail

Hidrogelovi za vaginalnu primjenu lijekova

The vaginal route of drug administration has been used for achieving local and systemic drug effects. The rate and extent of drug absorption after intravaginal application may be altered by vaginal physiology, age, stage in the menstrual cycle, pathological condition and formulation factors. Among a variety of vaginal dosage forms available, hydrogels offer several advantages such as hydrophilicity, biocompatibility, good distribution and retention, appropriate drug release and acceptability by patients. They have been mostly used for the treatment of vaginal dryness and local delivery of antimicrobial drugs, microbicides, contraceptives and labor inducers. However, hydrogels have also potential for systemic delivery of hormones, vaccines, proteins and peptides. This paper summarizes potentials, current use and research on hydrogels as vaginal drug delivery systems