Sposoby oceny jakości leków generycznych — od badania uwalniania do badania biorównoważności

Lek generyczny może się różnić od leku innowacyjnego (oryginalnego) składem jakościowym i ilościowym substancji pomocniczych oraz niewielkimi zmianami w sposobie wytwarzania substancji leczniczej. W badaniach biorównoważności in vivo, na podstawie profili stężeń we krwi, producent leku generycznego musi udowodnić, że te zmiany nie mają istotnego wpływu na wchłanianie ani na inne procesy farmakokinetyczne substancji czynnej. W określonych przypadkach (szczególnie dla substancji leczniczych dobrze rozpuszczalnych i szybko wchłaniających się) dopuszcza się określenie podobieństwa doustnych produktów leczniczych na podstawie badania uwalniania. Wyniki takiego testu in vitro nie mogą jednak stanowić dowodu podobieństwa lub różnicy w farmakokinetyce in vivo, jeżeli postacią leku jest tabletka lub kapsułka o przedłużonym albo kontrolowanym uwalnianiu, co omówiono na przykładzie preparatów z metoprololem

Postępy w wytwarzaniu pediatrycznych produktów leczniczych

W dniach 2-3 marca 2009 roku w Londynie odbyła się zorganizowana przez brytyjską Royal Pharmaceutical Society konferencja naukowa "Opracowywanie lepszych postaci leków dla dzieci" (Formulating better medicines for children). Tematyka konferencji objęła problemy bezpieczeństwa farmakoterapii dziecięcej i odpowiednich form przeznaczonych dla nich leków. W niniejszej pracy podjęto próbę streszczenia problemów poruszanych na konferencji oraz przeprowadzono przegląd literatury cytowanej przez prelegentów

Prototype gastro-resistant soft gelatin films and capsules-imaging and performance in vitro

The following study is a continuation of the previous work on preparation of gastro-resistant films by incorporation of cellulose acetate phthalate (CAP) into the soft gelatin film. An extended investigation on the previously described binary Gelatin-CAP and ternary Gelatin-CAP-carrageenan polymer films was performed. The results suggest that the critical feature behind formation of the acid-resistant films is a spinodal decomposition in the film-forming mixture. In the obtained films, upon submersion in an acidic medium, gelatin swells and dissolves, exposing a CAP-based acid-insoluble skeleton, partially coated by a residue of other ingredients. The dissolution-hindering effect appears to be stronger when iota-carrageenan is added to the film-forming mixture. The drug release study performed in enhancer cells confirmed that diclofenac sodium is not released in the acidic medium, however, at pH 6.8 the drug release occurs. The capsules prepared with a simple lab-scale process appear to be resistant to disintegration of the shell structure in acid, although imperfections of the sealing have been noticed

Controlled drug release by the pore structure in polydimethylsiloxane transdermal patches

The use of polydimethylsiloxanes (PDMS) as a drug carrier in transdermal adhesive patches is limited and there is insufficient data on the polymer structure and diffusivity, especially when additives modify the matrix. PDMS films with liquid additives (10% w/w): silicone oil (SO), polyoxyethylene glycol (PEG) or propylene glycol (PG) were prepared and indomethacin (IND; 5% w/w) was incorporated as a model active substance. The microstructure of the PDMS matrix and its permeability to water was investigated and correlated to the kinetics of the in-vitro IND release from the film. Three microscopic techniques were used to characterize in detail the microstructure of PDMS films: scanning electron microscopy, fluorescent microscopy and atomic force microscopy. PDMS films with hydrophilic PEG or PG showed different two-phase structures. A two-fold increase in steady-state flux of IND and increased water transport in the presence of PEG was attributed to the pore-like channels created by this polar solvent in the PDMS matrix. This effect was not observed in the films with PG, where only discontinuous droplet-like structures were visible. All additives significantly changed the tensile parameters of the films but the effects were not very pronounced

TLC determination of flavonoids from different cultivars of Allium cepa and Allium ascalonicum

This study comprises the optimization and validation of a new TLC method for determination of flavonols in the bulbs of seven cultivars of onions and shallots. Separation was performed on RP-18 plates with the solvent mixture tetrahydrofuran/water/formic acid (40+60+6, V/V/V) as a mobile phase. The method was validated for precision, linearity, LOD, LOQ, accuracy and robustness. Chromatographic analysis of the extracts revealed the presence of three main flavonols, quercetin, quercetin-4’-O-glucoside and quercetin-3,4’-O-diglucoside in the majority of analyzed cultivars. The content of flavonols in the analyzed extracts of onion bulbs varied from 123 (‘Exihibition’) to 1079 mg kg–1 fresh mass (fm) (‘Hybing’) in edible parts, and from 1727 (‘Hyline’) to 28949 mg kg–1 fm (‘Red Baron’) in outer scales. The bulbs of two shallot cultivars contained 209 (‘Ambition’) and 523 mg kg–1 fm (‘Matador’) of flavonols in edible parts and 5426 and 8916 mg kg–1 fm in outer scales, respectively

Gelatin Films Modified with Acidic and Polyelectrolyte Polymers—Material Selection for Soft Gastroresistant Capsules

The following investigation comprised the formation of acid-resistant gelatin-based films, intended for future use in soft-capsule technology. Such film compositions were obtained by including nonionized forms of acid-insoluble polymers in a gelatin-based film-forming mixture. The selected films were additionally modified with small amounts of anionic polysaccharides that have potential to interact with gelatin, forming polyelectrolyte complexes. The obtained film compositions were subjected to, e.g., disintegration tests, adhesiveness tests, differential scanning calorimetry (DSC), and a transparency study. As a result of the performed study, some commercial enteric polymers (acrylates), as well as cellulose acetate phthalate, were selected as components that have the ability to coalesce and form a continuous phase within a gelatin film. The use of a small amount (1.5%) of additional gelling polymers improved the rheological characteristics and adhesive properties of the obtained films, with ί-carrageenan and gellan gum appearing to be the most beneficial

Design of Experiments as a Tool to Optimize the Process of Coating Minitablets with Commercial Gastro-Resistant Coating Mixtures

According to the Quality by Design (QbD) concept, Design of Experiment (DoE) was used to indicate critical process parameters and optimize the fluid bed coating of minitablets in a laboratory size batch. Full factorial design was employed to increase knowledge of the process for three kinds of minitablet (MT) cores using two commercial gastro-resistant coating mixtures. The statistical analysis showed that different critical process parameters were indicated for the tested minitablets: X3: the coating mixture flow rate for MTs with pantoprazole sodium and Eudragit L; X2: the product temperature; X3 and X4: the spraying pressure for MTs with pantoprazole sodium and Acryl Eze II; and X1 and X2: MTs with diclofenac sodium. Such differences were the result of features, such as the sub-coat, size, and mass of the cores and the core and coating mixture composition. No optimal parameters were found for any of the tested MT types. Therefore, DoE should be considered as a statistical tool to individually optimize the process for the product, equipment, and tested parameters. However, optimization of the fluid bed coating allowed us to predict the values of the process parameters necessary to obtain good-quality products. Therefore, fluid bed coating may be successfully used to obtain modified-release MTs of high quality after applying the statistical tool DoE

Hydrogels - compounded dermatological preparations

Hydrogels are a physicochemical system in which an aqueous phase is gelled with a certain gelling polymer. They can make a good alternative to conventional lipophilic or absorption ointment bases, especially if the medicine should be administered to mucosa, because the gelling polymers interact with a mucose what results in mucoadhesion. The use of a hydrogel is preferred to lipophilic ointments in severe inflammations, exudative wounds, acne, oily skin or when the application area on the skin is hairy. Hydrogels also provide a cooling sensation on the skin, when water evaporates and this process is endothermic. Hydrogels are relatively popular also in a compounding practice in other countries, such as USA, where various types of commercially-made hydrogel bases are available. Despite the fact that hydrogels are accepted by law as compounded dosage forms, in Poland they have not been prepared in pharmacies because neither such bases nor suitable polymers are formally registered excipients for drug compounding, and the registration procedure is similar to the one for drug products authorization. The article describes hydrogels as there are first such materials available for pharmacists who are involved in compounding practice. Three gel-forming polymers: methylcellulose, hypromellose and hydroxyethylcellulose and hydrogel bases dedicated for drug compounding are characterized. Several examples of preparations with various active substances are presented and methods of their preparations are proposed. A dermatological base, Celugel, composed of hydroxyethylcellulose and recently registered in Poland for pharmacy compounding is also presented. Special attention is given to methods of hydrogel preparation, depending on the solubility profile of a certain type of polymer. Stability of the compounded hydrogels is discussed, especially regarding microbiological quality and the presence of preservatives. The benefits of these formulations are indicated including a relatively low cost of the hydrogel bases resulting from a low content of the polymers.Hydrożele dermatologiczne stanowią atrakcyjną alternatywę dla maści na podłożach lipofilowych oraz absorpcyjnych, szczególnie, gdy lek ma być podany na błony śluzowe. Łatwość sporządzenia hydrożelu oraz relatywnie niski koszt to dodatkowe zalety, jednak skomplikowany proces rejestracji polimerów żelujących jako substancji do receptury w Polsce skutkuje brakiem surowców do sporządzania nowoczesnych hydrożeli. Niniejszy artykuł ma na celu przybliżenie postaci hydrożelu w kontekście preparatyki recepturowej w sytuacji, gdy zaczęły być dostępne pierwsze takie surowce

Problems in pharmaceutical compounding of eye-drops with cyclosporine A

Cyclosporine A is very effective in treatment of many ophthalmic pathologies like immunological and inflammatory diseases of the cornea, conjunctive or uvea. It is also used to prevent corneal graft rejection and to treat dry eye syndrome. Local ocular administration significantly reduces the risk of systemic side effects. Currently on the market are two products in the form of eye drops: Restasis® (0.05% of cyclosporine) in US and Ikervis® (0.1% of cyclosporine) in the EU. Both are in the form of oil-in-water emulsion. Their availability is still limited and cyclosporine concentration is low. This is a reason that compounded formulations are prepared in hospital and retail pharmacies. The pharmacists do not have an access to the substance and use injectable (50 mg/ml cyclosporine), oral solutions (100 mg/ml cyclosporine) or even oral capsules (25-100 mg/capsule) as the source of cyclosporine. That allows to use of cyclosporine for topical ophthalmic applications in varies formulations, indications, concentration and posology. Due to the fact that cyclosporine is a highly lipophilic and poorly water soluble, it is mostly compounded and administered as an oily solution. Unfortunately, that dosage form is poorly tolerated after administration to the eye, mainly due to the fact of blurring vision commonly observed because of the high viscosity of the oils. However, for many patients use of compounded eye drops with cyclosporine can be the only hope to alleviate the symptoms of the disease, and sometimes even to avoid vision loss. When pharmaceutical compounding of eye drops with cyclosporine, the problem is the presence of auxiliary substances such as, for example, Cremophor, ethanol evaporation, or obtaining the exact dose of the active substance from capsules. This article gives an overview of different approaches for compounding of the cyclosporine eye drops in hospital and retail pharmacies using marketed products off-label. Benefits and the limitations of each method are presented with comments regarding the proper drug compounding.Cyklosporyna A jest skuteczna w leczeniu wielu chorób oczu, takich jak choroby immunologiczne i zapalne rogówki, spojówki czy naczyniówki. Jest również stosowana w zapobieganiu odrzucenia przeszczepu rogówki i leczeniu zespołu suchego oka. Preferowane jest miejscowe podanie cyklosporyny bezpośrednio do oka, by zmniejszyć ryzyko wystąpienia ogólnoustrojowych działań niepożądanych. Ze względu na ograniczoną dostępność gotowych kropli do oczu z cyklosporyną, zwłaszcza w wyższym stężeniu (0,5-2%), w aptekach szpitalnych i ogólnodostępnych sporządzane są recepturowe krople do oczu z wykorzystaniem roztworu do wstrzykiwań lub roztworu doustnego jako źródła cyklosporyny. Niniejszy artykuł stanowi przegląd różnych metod sporządzania recepturowych kropli do oczu z preparatów handlowych cyklosporyny, z omówieniem ich zalet i ograniczeń, jak również zawiera wskazówki dotyczące właściwego postępowania przy sporządzaniu takich kropli

Influence of Experimental Conditions on Electronic Tongue Results—Case of Valsartan Minitablets Dissolution

A potentiometric electronic tongue was applied to study the release of valsartan from pharmaceutical formulations, i.e., minitablets uncoated and coated with Eudragit E. Special attention was paid to evaluate the influence of medium temperature and composition, as well as to compare the performances of the sensor arrays working in various hydrodynamic conditions. The drug dissolution profiles registered with the ion-sensitive electrodes were compared with standard dissolution tests performed with USP Apparatus 2 (paddle). Moreover, the signal changes of all sensors were processed by principal component analysis to visualize the release modifications, related to the presence of the coating agent. Finally, the importance and influence of the experimental conditions on the results obtained using potentiometric sensor arrays were discussed