Development of suitable working Protocol for in vitro Tape Stripping: A Case Study with biocompatible Aceclofenac-loaded topical Nanoemulsions

Considering the numerous organizational and legislative issues associated with in vivo studies, the present study aimed to develop in vitro tape stripping protocol that could serve as a prospective technique for skin penetration studies. The research was mainly focused on the suitability of transepidermal water loss (TEWL) measurements, as a barrier integrity test for porcine ear skin subjected to freezing/thawing procedure, as well as on the selection of the most suitable device for pressing adhesive tapes onto the porcine ear surface during skin stripping procedure. Obtained results suggest that TEWL measurements were able to detect the damage of the stratum corneum (SC) caused by physical impairment (using adhesive tapes) and tissue degradation/dehydration (prolonged storage at –20ºC/ambient conditions). Penetration profiles of aceclofenac from nanoemulsions based on sucrose esters or polysorbate 80 as coemulsifiers, obtained in vitro (using a roller as pressure device), were in a good agreement with data obtained in vivo on humans, supporting the use of developed in vitro tape-stripping protocol in skin formulation development and optimization

The implications of regulatory framework for topical semisolid drug products: From critical quality and performance attributes towards establishing bioequivalence

Due to complex interdependent relationships affecting their microstructure, topical semisolid drug formulations face unique obstacles to the development of generics compared to other drug products. Traditionally, establishing bioequivalence is based on comparative clinical trials, which are expensive and often associated with high degrees of variability and low sensitivity in detecting formulation differences. To address this issue, leading regulatory agencies have aimed to advance guidelines relevant to topical generics, ultimately accepting different non-clinical, in vitro/in vivo surrogate methods for topical bioequivalence assessment. Unfortunately, according to both industry and academia stakeholders, these efforts are far from flawless, and often upsurge the potential for result variability and a number of other failure modes. This paper offers a comprehensive review of the literature focused on amending regulatory positions concerning the demonstration of (i) extended pharmaceutical equivalence and (ii) equivalence with respect to the efficacy of topical semisolids. The proposed corrective measures are disclosed and critically discussed, as they span from mere demands to widen the acceptance range (e.g., from 10% to 20%/25% for rheology and in vitro release parameters highly prone to batch-to-batch variability) or reassess the optimal number of samples required to reach the desired statistical power, but also rely on specific data modeling or novel statistical approaches

Towards optimal ph of the skin and topical formulations: From the current state of the art to tailored products

Acidic pH of the skin surface has been recognized as a regulating factor for the maintenance of the stratum corneum homeostasis and barrier permeability. The most important functions of acidic pH seem to be related to the keratinocyte differentiation process, the formation and function of epidermal lipids and the corneocyte lipid envelope, the maintenance of the skin microbiome and, consequently, skin disturbances and diseases. As acknowledged extrinsic factors that affect skin pH, topically applied products could contribute to skin health maintenance via skin pH value control. The obtained knowledge on skins’ pH could be used in the formulation of more effective topical products, which would add to the development of the so-called products ‘for skin health maintenance’. There is a high level of agreement that topical products should be acidified and possess pH in the range of 4 to 6. However, formulators, dermatologists and consumers would benefit from some more precise guidance concerning favorable products pH values and the selection of cosmetic ingredients which could be responsible for acidification, together with a more extensive understanding of the mechanisms underlaying the process of skin acidification by topical products

Nano-and microcarriers as drug delivery systems for usnic acid: Review of literature

Usnic acid is one of the most investigated lichen secondary metabolites, with several proven biological properties with potential medical relevance. However, its unfavorable physico-chemical properties, as well as observed hepatotoxicity, have discouraged wide-range utilization of usnic acid as a promising therapeutic agent. In accordance with the growing research interest in the development of nanotechnology, especially in the arena of preparations based on natural sources of medicinal compounds, usnic acid incorporated into nano-and microsized colloidal carriers has been a subject of a large number of publications. Therefore, this review discusses the overall results of the studies dealing with usnic acid encapsulated into lipid-based, polymeric and nonorganic micro-and/or nanocarriers, as potential drug delivery systems for this natural compound, in an attempt to introduce its usage as a potential antitumor, antimicrobial, wound-healing, antioxidative and anti-inflammatory drug

A comparison of Myribase and Doublebase gel: Does qualitative similarity of emollient products imply their direct interchangeability in everyday practice?

Emollients are acknowledged as a part of standard care in therapeutic and prevention protocols as well as a part of everyday skin care routine. When it comes to making a final decision between two emollient products, the ingredient list, that is, the formulation composition could be the determining factor. In such cases the consumer, and some healthcare providers, believe that products with the same qualitative composition (ingredient list) must have the same efficacy. In this study, we have investigated the skin hydration performance of two emollient preparations (DBG and MBG), which appear to contain the same ingredients, and hence, could be considered interchangeable in everyday practice. Our studies showed that the effects of DBG were overall superior to the ones attributed to MBG at each investigated time point (1, 2, 4, and 24 h post application) when tested on normal and dry skin. Consequently, it is shown that two apparently qualitatively identical products do not necessarily provide matching efficacy

Farmaceutski oblici bioloških i drugih lekova u terapiji multiple skleroze

Multiple sclerosis (MS) treatment options include several biologic and numerous non- biologic drugs. Although three recombinant preparations of interferon-beta (IFN-β) represent the cornerstone of the disease-modifying therapy, the introduction of pegylated IFN-β-1a should ensure a less frequent drug administration. At the moment, natalizumab is the sole monoclonal antibody registered for relapsing-remitting MS in our country. Even though the biologics are primarily limited to parenteral routes of administration, symptomatic therapy, which aims to alleviate or eliminate the accompanying symptoms that deteriorate quality of life, encompasses diverse dosage forms for oral (tablets, film-coated tablets), sublingual (oral lyophilisate) or nasal (nasal spray) administration. Due to considerable in vitro and in vivo instability, formulation of delivery systems for biologics is primarily focused on preserving their physicochemical stability. The selection of excipients is commonly related to pH value adjustment, solubility modification and anti- adsorption/anti-agregation behaviour of proteins. As for the lyophilised forms, the focus is on cryo/lyoprotectants, collapse temperature modifiers and appropriate fillers. The selection of suitable sterilization procedure is of the utmost importance, and has resulted in the development of single use systems (SUS) technologies. Therefore, pharmacists should be familiar with optimal storage and handling conditions for these drugs, before, during and after reconstitution, as well as upon their administration.Terapija multiple skleroze obuhvata nekoliko bioloških i veći broj ne-bioloških lekova. Iako su tri rekombinantna preparata interferona-beta (IFN-β) okosnica terapije koja modifikuje prirodni tok bolesti, uvođenje pegilovane forme IFN-β-1a omogućilo bi manje frekventnu primenu leka. Za sada, natalizumab je jedino monoklonsko antitelo odobreno za terapiju relapsno-remitentne forme bolesti u našoj zemlji. Iako je terapija biološkim lekovima ograničena na parenteralni put primene, simptomatska terapija, sa ciljem ublažavanja ili eliminisanja simptoma bolesti koji smanjuju funkcionlanost i remete kvalitet života obolelih, pruža mogućnost primene različitih farmaceutskih oblika za peroralnu (tablete, film tablete), sublingvalnu (oralni liofilizat) ili nazalnu (sprej za nos) primenu. Zbog velike in vitro i in vivo nestabilnosti, formulacija farmaceutskih oblika bioloških lekova primarno je orijentisana na očuvanje njihove fizičko-hemijske stabilnosti, te je izbor ekscipijenasa obično vezan za podešavanje pH i modifikovanje rastvorljivosti i anti- adsorpciono/anti-agregaciono ponašanje proteina. Kod liofilizovanih oblika (praškova) fokus je na krio/lioprotektantima, modifikatorima temperaturnog kolapsa i prihvatljivim puniocima. Uz to, velika pažnja posvećuje se izboru adekvatnog postupka sterilizacije, pa se poslednjih godina razvijaju sistemi za aseptičnu proizvodnju sa jednokratnom upotrebom (engl. single use systems - SUS tehnologije). Od farmaceuta se očekuje poznavanje optimalnih uslova za čuvanje i rukovanje ovim lekovima, pre, tokom i nakon rekonstitucije, kao i tokom njihove primene

Hormoni kao biotehnološki lekovi - humani insulin i analozi

Biotech-drugs or biopharmaceuticals are proteins or nucleic acids, which have been produced by living organisms as a result of biotechnology. Three decades after the beginning steps, they make a third part of all new drugs appearing each year at the world market. The era of animal source insulins has passed away and human recombinant DNA insulin and insulin analogues, as biopharmaceutics of the first and second generations, respectively, are the cornerstone of the diabetes mellitus current therapy. All insulin preparations are divided into three groups: 1) short - and rapid-acting insulins; 2) intermediate-acting insulins and 3) long-acting insulins. Short-acting human insulins and rapid-acting analogous insulin lispro, aspart and glulisine are available in form of solution for injections. In order to achieve the intermediate duration of action, human insulin is co-crystallized with protamine (insulin isophane suspensions) or human insulins and rapid-acting analogues are prepared as mixtures of isophane insulin suspension and monomer soluble form in fixed-ratios (75/25, 70/30, 50/50). The currently available long-acting insulins are analogues insulin glargine and insulin detemir, whereas use of amorphous and crystalline insulin zinc suspensions (lente and ultralente insulins) for prolonged action is now very rare, because of insufficiently favorable pharmacokinetics. Similarly, inhalation administration of insulin, although introduced into clinical practice, did not show the expected benefits in comparison to the conventional parenteral use.Biotehnološki lekovi ili biofarmaceutici su proteini ili nukleinske kiseline koje proizvode živi organizmi primenom biotehnoloških postupaka. Tri decenije nakon početnih koraka, oni čine trećinu svih novih lekova koji se svake godine pojave na tržištu u svetu. Era insulina životinjskog porekla je prošla i humani insulin dobijen rekombinantnom DNK tehnologijom i insulinski analozi, kao biotehnološki lekovi prve, odnosno druge generacije, čine osnovu savremene terapije dijabetes melitusa. Svi preparati insulina dele se u tri osnovne grupe: 1) kratko - i brzo-delujuće insuline; 2) srednje-delujuće insuline; 3) dugo-delujuće insuline. Kratko-delujući humani insulin i brzo-delujući analozi insulin lispro, insulin aspart i insulin glulizin prisutni su u obliku rastvora za injekcije. U cilju postizanja srednje dužine dejstva humani insulin se formuliše kao kokristalizat sa protaminom (insulin izofan suspenzija) ili se humani insulin i brzo-delujući analozi pripremaju kao mešavine insulin izofan suspenzije i monomernog rastvornog oblika u određenim odnosima (75/25, 70/30, 50/50). Kao dugo-delujući insulini primenjuju se analozi insulin glargin i insulin detemir, dok se produženje dejstva stvaranjem amorfne ili kristalne insulin cink suspenzije (lente i ultralente insulin) sve manje koristi, zbog nedovoljno povoljne farmakokinetike. Slično, inhalaciona primena insulina, iako uvedena u kliničku praksu, nije pokazala očekivane prednosti u odnosu na konvencionalnu parenteralnu primenu

Procena stabilnosti emulzionih preparata za topikalnu primenu - vrednost dinamičkomehaničkog termoanalitičkog (DMTA) testa kao brze reološke alternative konvencionalnom testu smrzavanje-odmrzavanje

The assessment of stability in emulsion-based topical preparations can be approached through real-time monitoring and/or accelerated methods, drawing predictions from pertinent stability-related physicochemical parameters. Ensuring the robustness and durability of topical products during storage, transport, and application necessitates thorough stability testing. However, due to the diversity of emulsion types and their intended use, there is no universal standard test, placing the liability on formulators/manufacturer to tailor appropriate assessments. Notably, topical emulsions, particularly cosmetic variants, often exhibit impressive stability with extended shelf lives. Nonetheless, evaluating their stability and decision-making remain challenging and time-consuming in industrial contexts. This underscores the demand for alternative testing protocols that expedite stability assessments and predict emulsion-based product stability accurately. This article comprehensively surveys literature, enriched with practical insights, exploring core mechanisms behind emulsion stability and prevention of instability. The discussion encompasses diverse approaches to stability assessment, revealing methodologies and parameters under examination during testing. Particular focus is placed on the dynamic-mechanical thermoanalysis (DMTA) method explored as a rapid, rheologically-based alternative to the conventional freeze-thaw test, emphasizing its usefulness for expediting the stability evaluation of emulsion-based topical preparations.Procena stabilnosti emulzionih preparata za topikalnu primenu može se sprovesti praćenjem promena u realnom vremenu i/ili primenom ubrzanih metoda, te predviđanjem stabilnosti i roka trajanja proizvoda na osnovu merenja relevantnih fizičkohemijskih parametara tokom ispitivanja. Kako bi se obezbedila robusnost i dugoročnost emulzionih proizvoda za kožu tokom čuvanja, transporta i primene, neophodno je sprovesti pažljivo isplanirano, opsežno ispitivanje stabilnosti. Međutim, imajući u vidu različite tipove emulzija i njihovu namenu, ne postoji univerzalni standardni protokol za ispitivanje stabilnosti, što formulatore/proizvođača čini odgovornim kada je u pitanju izbor odgovarajućeg testa i metodologije. Evidentno je da emulzije za topikalnu primenu, a posebno kozmetičke emulzije, često pokazuju visoku stabilnost sa dugim rokovima upotrebe. S druge strane, procena stabilnosti ovakvih emulzija i donošenje odgovarajućih odluka i dalje ostaje izazov u industrijskom okruženju i zahteva dosta vremena, što nameće potrebu za alternativnim protokolima koji omogućavaju ubrzano ispitivanje, ali i uspešno predviđanje stabilnosti emulzionih proizvoda. Prikazani rad daje sveobuhvatni pregled literature prožet praktičnim pogledima na ključne fenomene odgovorne za stabilnost emulzija, zatim daje uvid u različite pristupe za procenu njihove stabilnosti, uključujući metodologije koje se koriste i parametre koji se prate tokom ispitivanja. Rad u poseban fokus stavlja dinamičko-mehanički termoanalitički (DMTA) metod kao brzu reološku alternativu konvencionalnom testu smrzavanje-odmrzavanje, posebno ističući primenljivost metoda za ubrzano ispitivanje stabilnosti emulzionih preparata za topikalnu primenu

Farmaceutsko-tehnološki aspekti lekova u inhalacionoj terapiji astme u dece

Inhalation is the preferred route for asthma therapy, since it offers a rapid onset of drug action, requires smaller doses, and reduces systemic effects compared with other routes of administration. Unfortunately, inhalation devices are frequently used in an empirical manner rather than on evidence-based awareness. Metered-dose inhalers (MDI) are practical, cheap and multidose. However, there are several problems with their use. Breath-actuated MDI are easy to use and can be activated by very low flow. However, young children may not be able to use them efficiently. The use of spacers reduces oropharyngeal deposition and improves drug delivery to the lung. Spacers do not require patient coordination, but some general rules must be followed for their optimal use. Dry powder inhalers (DPI) are portable and easy to use. They are indicated either for rescue bronchodilators therapy or for regular treatment with inhaled corticosteroids and long-acting bronchodilators. For the application of liquid preparation for inhalation a wide variety of nebulizers are available in asthma therapy. The choice of a delivery device mainly depends on the age of the patient, the drug to be administered and the condition to be treated. As the therapy efficacy mainly depends on drug device optimal use, proper education of pharmacist and his rediness/duty to demonstrate the device usage is also essential for children and parents, too.Budući da ima niz prednosti, inhalacioni put primene lekova je prvi izbor u terapiji hronične astme: brz početak delovanja leka, a potrebne su niže doze i time manja mogućnost ispoljavanja neželjenih efekata u poređenju sa dragim putevima primene. Nažalost, pomoćni uređaji za inhalaciju češće se koriste empirijski nego na osnovu kliničkih dokaza. Merno-dozni inhalatori (MDI), sprejovi za inhalaciju su još uvek široko rasprostranjen vid inhalacione primene lekova u terapiji astme. Praktični su, jevtini i višedozni sistemi. Međutim, postoji nekoliko problema vezano za njihovu primenu. Udahom-aktivirani MDI su jednostavni za primenu i mogu se aktivirati pri veoma slabom udanu. Nažalost, mala deca ih ne mogu koristiti efikasno. Upotrebom komora redukuje se deponovanje lekova u orofarinksu i poboljšava raspodela leka u pluća. Komore ne zahtevaju koordinaciju pokreta na relaciji raspršivanje/inhalacija od strane pacijenta, ali se neka generalna pravila moraju poštovati u cilju postizanja očekivanog terapijskog odgovora. Praškovi za inhalaciju (DPI) su laki za primenu i prihvatljive su veličine. Indikovani su u akutnim stanjima za primenu bronhodilatatora ili za terapiju održavanja kod hronične astme, koja se tretira kortikosteroidima ili dugo-delujućim bronhodilatatorima. U terapiji astme na raspolaganju je nekoliko tipova nebulizera za primenu tečnih preparata za inhalaciju. Izbor optimalnog uređaja uglavnom zavisi od uzrasta deteta, leka koji treba da se primeni i stanja koje treba tretirati. Budući da efekat terapije u velikoj meri zavisi od načina upotrebe uređaja za inhalaciju, adekvatna edukacija farmaceuta i njegova obučenost i spremnost/obaveza da pacijentu demonstrira primenu preparata je od izuzetne važnosti i za decu i za roditelje