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1.
J Pharm Sci ; 100(6): 2054-63, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21491435

RESUMO

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing lamivudine as the only active pharmaceutical ingredient were reviewed. The solubility and permeability data of lamivudine as well as its therapeutic index, its pharmacokinetic properties, data indicating excipient interactions, and reported BE/bioavailability (BA) studies were taken into consideration. Lamivudine is highly soluble, but its permeability characteristics are not well-defined. Reported BA values in adults ranged from 82% to 88%. Therefore, lamivudine is assigned to the biopharmaceutics classification system (BCS) class III, noting that its permeability characteristics are near the border of BCS class I. Lamivudine is not a narrow therapeutic index drug. Provided that (a) the test product contains only excipients present in lamivudine IR solid oral drug products approved in the International Conference on Harmonization or associated countries in usual amounts and (b) the test product as well as the comparator product fulfills the BCS dissolution criteria for very rapidly dissolving; a biowaiver can be recommended for new lamivudine multisource IR products and major post-approval changes of marketed drug products.


Assuntos
Lamivudina/administração & dosagem , Lamivudina/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Fenômenos Químicos , Excipientes , Humanos , Lamivudina/química , Lamivudina/toxicidade , Solubilidade , Equivalência Terapêutica , Distribuição Tecidual
2.
J Pharm Sci ; 100(1): 11-21, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20602454

RESUMO

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing mefloquine hydrochloride as the only active pharmaceutical ingredient (API) are reviewed. The solubility and permeability data of mefloquine hydrochloride as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability studies were taken into consideration. Mefloquine hydrochloride is not a highly soluble API. Since no data on permeability are available, it cannot be classified according to the Biopharmaceutics Classification System with certainty. Additionally, several studies in the literature failed to demonstrate BE of existing products. For these reasons, the biowaiver cannot be justified for the approval of new multisource drug products containing mefloquine hydrochloride. However, scale-up and postapproval changes (HHS-FDA SUPAC) levels 1 and 2 and most EU type I variations may be approvable without in vivo BE, using the dissolution tests described in these regulatory documents.


Assuntos
Antimaláricos/administração & dosagem , Antimaláricos/farmacocinética , Mefloquina/administração & dosagem , Mefloquina/farmacocinética , Administração Oral , Animais , Antimaláricos/química , Antimaláricos/uso terapêutico , Disponibilidade Biológica , Formas de Dosagem , Aprovação de Drogas , Excipientes , Humanos , Mefloquina/química , Mefloquina/uso terapêutico , Solubilidade , Equivalência Terapêutica
3.
J Pharm Sci ; 100(1): 22-33, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20602455

RESUMO

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing ciprofloxacin hydrochloride as the only active pharmaceutical ingredient (API) are reviewed. Ciprofloxacin hydrochloride's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. Solubility and BA data indicate that ciprofloxacin hydrochloride is a BCS Class IV drug. Therefore, a biowaiver based approval of ciprofloxacin hydrochloride containing IR solid oral dosage forms cannot be recommended for either new multisource drug products or for major scale-up and postapproval changes (variations) to existing drug products.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Ciprofloxacina/administração & dosagem , Ciprofloxacina/farmacocinética , Administração Oral , Animais , Antibacterianos/química , Antibacterianos/uso terapêutico , Disponibilidade Biológica , Ciprofloxacina/química , Ciprofloxacina/uso terapêutico , Formas de Dosagem , Aprovação de Drogas , Excipientes , Humanos , Absorção Intestinal , Permeabilidade , Solubilidade , Equivalência Terapêutica
4.
J Pharm Sci ; 99(6): 2544-56, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19960529

RESUMO

Literature and new experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing furosemide are reviewed. The available data on solubility, oral absorption, and permeability are sufficiently conclusive to classify furosemide into Class IV of the Biopharmaceutics Classification System (BCS). Furosemide's therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems are also taken into consideration. In view of the data available, it is concluded that the biowaiver procedure cannot be justified for either the registration of new multisource drug products or major postapproval changes (variations) to existing drug products.


Assuntos
Furosemida/farmacocinética , Disponibilidade Biológica , Biofarmácia , Formas de Dosagem , Excipientes , Humanos , Permeabilidade , Solubilidade , Equivalência Terapêutica
5.
J Pharm Sci ; 99(4): 1639-53, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19798752

RESUMO

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing doxycycline hyclate are reviewed. According to the Biopharmaceutics Classification System (BCS), doxycycline hyclate can be assigned to BCS Class I. No problems with BE of IR doxycycline formulations containing different excipients and produced by different manufacturing methods have been reported and hence the risk of bioinequivalence caused by these factors appears to be low. Doxycycline has a wide therapeutic index. Further, BCS-based dissolution methods have been shown to be capable of identifying formulations which may dissolve too slowly to generate therapeutic levels. It is concluded that a biowaiver is appropriate for IR solid oral dosage forms containing doxycycline hyclate as the single Active Pharmaceutical Ingredient (API) provided that (a) the test product contains only excipients present in doxycycline hyclate IR solid oral drug products approved in the International Conference on Harmonization (ICH) or associated countries; and (b) the comparator and the test products comply with the BCS criteria for "very rapidly dissolving" or, alternatively, when similarity of the dissolution profiles can be demonstrated and the two products are "rapidly dissolving.".


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Doxiciclina/análogos & derivados , Antibacterianos/química , Antibacterianos/uso terapêutico , Formas de Dosagem , Doxiciclina/administração & dosagem , Doxiciclina/química , Doxiciclina/farmacocinética , Doxiciclina/uso terapêutico , Aprovação de Drogas , Humanos , Solubilidade , Equivalência Terapêutica
6.
J Pharm Sci ; 98(7): 2252-67, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19160441

RESUMO

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing rifampicin as the only Active Pharmaceutical Ingredient (API) are reviewed. Rifampicin's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. Solubility and absolute BA data indicate that rifampicin is a BCS Class II drug. Of special concern for biowaiving is that many reports of failure of IR solid oral dosage forms of rifampicin to meet BE have been published and the reasons for these failures are yet insufficiently understood. Moreover, no reports were identified in which in vitro dissolution was shown to be predictive of nonequivalence among products. Therefore, a biowaiver based approval of rifampicin containing IR solid oral dosage forms cannot be recommended for either new multisource drug products or for major scale-up and postapproval changes (variations) to existing drug products.


Assuntos
Antibióticos Antituberculose/administração & dosagem , Antibióticos Antituberculose/farmacocinética , Hansenostáticos/administração & dosagem , Hansenostáticos/farmacocinética , Rifampina/administração & dosagem , Rifampina/farmacocinética , Administração Oral , Antibióticos Antituberculose/química , Antibióticos Antituberculose/uso terapêutico , Disponibilidade Biológica , Formas de Dosagem , Aprovação de Drogas , Estabilidade de Medicamentos , Excipientes , Interações Alimento-Droga , Humanos , Hansenostáticos/química , Hansenostáticos/uso terapêutico , Permeabilidade , Rifampina/química , Rifampina/uso terapêutico , Solubilidade , Equivalência Terapêutica
7.
J Pharm Sci ; 98(7): 2238-51, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18979535

RESUMO

Literature data are reviewed relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing quinidine sulfate. Quinidine sulfate's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. The available data are not fully conclusive, but do suggest that quinidine sulfate is highly soluble and moderately to highly permeable and would likely be assigned to BCS Class I (or at worst BCS III). In view of the inconclusiveness of the data and, more important, quinidine's narrow therapeutic window and critical indication, a biowaiver based approval of quinidine containing dosage forms cannot be recommended for either new multisource drug products or for major postapproval changes (variations) to existing drug products.


Assuntos
Antiarrítmicos/administração & dosagem , Antiarrítmicos/farmacocinética , Antimaláricos/administração & dosagem , Antimaláricos/farmacocinética , Quinidina/administração & dosagem , Quinidina/farmacocinética , Administração Oral , Antiarrítmicos/química , Antiarrítmicos/uso terapêutico , Antimaláricos/química , Antimaláricos/uso terapêutico , Disponibilidade Biológica , Formas de Dosagem , Aprovação de Drogas , Excipientes , Humanos , Permeabilidade , Quinidina/química , Quinidina/uso terapêutico , Solubilidade , Equivalência Terapêutica
8.
J Control Release ; 134(1): 11-7, 2009 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-19014985

RESUMO

The aim of this investigation was to design a novel Gas Empowered Drug Delivery (GEDD) system for CO(2) forced transport of peptide drugs together with mucoadhesive polymers to the surface of the small intestine. The GEDD effect of the core tablet was achieved using CO(2) gas to push insulin together with the mucoadhesive excipients poly(ethyleneoxide) (PEO) and the permeation enhancer trimethyl chitosan (TMC) to the surface of the small intestine. The in-vitro insulin release showed that almost 100% of the insulin was released from enterically coated tablets within 30 min at pH 6.8. The designed GEDD system was shown to increase the insulin transport by approximately 7 times in comparison with the free insulin across sheep's intestine ex-vivo. Three different peroral formulations were administered to male rabbits: F1 containing no TMC or PEO, F2 containing PEO but no TMC and F3 containing both PEO and TMC. The administrations of insulin using the formulation F1 resulted in a low FR value of 0.2%+/-0.1%, while the formulations F2 and F3 resulted in a much higher FR values of 0.6+/-0.2% and 1.1%+/-0.4%, respectively. Hence, the insulin permeation achieved by the GEDD system is primarily due to the enhancing effect of TMC and the mucoadhesive properties of PEO both of which synergistically increase the bioavailability of insulin.


Assuntos
Dióxido de Carbono/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Insulina/administração & dosagem , Insulina/farmacocinética , Intestino Delgado/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Quitosana/farmacologia , Avaliação Pré-Clínica de Medicamentos , Mucosa Gástrica/metabolismo , Insulina/sangue , Absorção Intestinal/efeitos dos fármacos , Intestino Delgado/metabolismo , Masculino , Coelhos , Ovinos , Estômago/efeitos dos fármacos
9.
J Pharm Sci ; 98(4): 1206-19, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18752289

RESUMO

Literature data are reviewed regarding the scientific advisability of allowing a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing either diclofenac potassium and diclofenac sodium. Within the biopharmaceutics classification system (BCS), diclofenac potassium and diclofenac sodium are each BCS class II active pharmaceutical ingredients (APIs). However, a biowaiver can be recommended for IR drug products of each salt form, due to their therapeutic use, therapeutic index, pharmacokinetic properties, potential for excipient interactions, and performance in reported BE/bioavailability (BA) studies, provided: (a) test and comparator contain the same diclofenac salt; (b) the dosage form of the test and comparator is identical; (c) the test product contains only excipients present in diclofenac drug products approved in ICH or associated countries in the same dosage form, for instance as presented in this paper; (d) test drug product and comparator dissolve 85% in 30 min or less in 900 mL buffer pH 6.8, using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm; and (e) test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Diclofenaco/administração & dosagem , Diclofenaco/farmacocinética , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/química , Disponibilidade Biológica , Fenômenos Químicos , Diclofenaco/efeitos adversos , Diclofenaco/química , Excipientes/química , Humanos , Solubilidade , Comprimidos , Equivalência Terapêutica
10.
Eur J Pharm Biopharm ; 70(1): 270-8, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18492606

RESUMO

In this study four quaternized derivatives of chitosan: trimethyl chitosan (TMC), dimethylethyl chitosan (DMEC), diethylmethyl chitosan (DEMC) and triethyl chitosan (TEC) with degree of substitution of approximately 50+/-5% were synthesized and their effect on the permeability of insulin across intestinal Caco-2 monolayers was studied and compared with chitosan both in free-soluble form and in nanoparticulate systems. Transepithelial electrical resistance (TEER) studies revealed that all four chitosan derivatives in free-soluble forms were able to decrease the TEER value in the following order TMC>DMEC>DEMC=TEC>chitosan, indicating their abilities to open the tight junctions. Recovery studies on the TEER showed that the effect of the polymers on Caco-2 cell monolayer is reversible and proves the viability of cells after incubation with all polymers. A similar rank order was also observed when measuring the zeta-potentials of the various polymers in solution form. Transport studies of insulin together with the soluble polymers across Caco-2 cell layers showed the following ranking: TMC>DMEC>DEMC>TEC>chitosan which is in agreement with the strength of the cationic charge of the polymer. In comparison to the free-soluble polymers, the nanoparticles prepared by ionic gelation of the chitosan and its quaternized derivatives had much lower effect on decreasing the TEER by opening of the tight junctions. This can be explained by the reduced available amount of positive charge at the surface of the nanoparticles. In accordance with these results, the insulin loaded nanoparticles showed much less permeation across the Caco-2 cell monolayer in comparison to the free-soluble polymers. Mass balance transport studies revealed that a substantial amount of the nanoparticles has been entrapped into the Caco-2 monolayer or attached to the cell surface. It can thus be stated that while free-soluble polymers can reversibly open the tight junctions and increase the permeation of insulin, the nanoparticles had basically only a low effect on the opening of the tight junction and the paracellular transport of insulin across the Caco-2 cell monolayer. These data convincingly show that nanoparticles consisting of chitosan and its quaternary ammonium derivatives loaded with insulin are less effective in facilitating paracellular transport across Caco-2 cell monolayers than the corresponding free polymers.


Assuntos
Quitosana/farmacologia , Portadores de Fármacos , Insulina/metabolismo , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Nanopartículas , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Quitosana/análogos & derivados , Quitosana/síntese química , Quitosana/toxicidade , Impedância Elétrica , Humanos , Mucosa Intestinal/metabolismo , Cinética , Permeabilidade , Solubilidade , Propriedades de Superfície , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo
11.
J Pharm Sci ; 97(12): 5061-73, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18425814

RESUMO

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing (biowaiver) for the approval of immediate release (IR) solid oral dosage forms containing aciclovir are reviewed. Aciclovir therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) studies were also taken into consideration in order to ascertain whether a biowaiver can be recommended. According to the Biopharmaceutics Classification System (BCS) and considering tablet strengths up to 400 mg, aciclovir would be BCS Class III. However, in some countries also 800 mg tablets are available which fall just within BCS Class IV. Aciclovir seems not to be critical with respect to a risk for bioinequivalence, as no examples of bioinequivalence have been identified. It has a wide therapeutic index and is not used for critical indications. Hence, if: (a) the test product contains only excipients present in aciclovir solid oral IR drug products approved in ICH or associated countries, for instance as presented in this article; and (b) the comparator and the test product both are very rapidly dissolving, a biowaiver for IR aciclovir solid oral drug products is considered justified for all tablet strengths.


Assuntos
Aciclovir/administração & dosagem , Antivirais/administração & dosagem , Aciclovir/farmacocinética , Administração Oral , Antivirais/farmacocinética , Disponibilidade Biológica , Equivalência Terapêutica
12.
J Pharm Sci ; 97(9): 3691-9, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18257031

RESUMO

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing acetazolamide are reviewed. Acetazolamide's solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems are taken into consideration. The available data on solubility, on oral absorption and permeability are not sufficiently conclusive to classify acetazolamide with certainty. Taking a conservative approach, no biowaiver is considered justified for the registration of new multisource drug products. However, SUPAC level 1 and level 2 postapproval changes and most EU Type I variations can be approved waiving in vivo BE studies.


Assuntos
Acetazolamida/administração & dosagem , Inibidores da Anidrase Carbônica/administração & dosagem , Acetazolamida/farmacocinética , Administração Oral , Inibidores da Anidrase Carbônica/farmacocinética , Formas de Dosagem , Excipientes , Humanos , Solubilidade , Equivalência Terapêutica
13.
J Pharm Sci ; 97(9): 3709-20, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18271031

RESUMO

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing pyrazinamide as the only active pharmaceutical ingredient (API) are reviewed. Pyrazinamide is BCS Class III, with linear absorption over a wide dosing range. The risk of bioinequivalence is estimated to be low. Depending on the definition used, pyrazinamide can be classified as a narrow therapeutic index (NTI) drug, which is usually a caveat to biowaiving but may be deemed acceptable if the Summary of Product Characteristics (SmPCs) of the test product stipulates the need for regular monitoring of liver function. It is concluded that a biowaiver can be recommended for IR solid oral dosage only when the test product (a) contains only excipients present in pyrazinamide IR solid oral drug products approved in ICH or associated countries, (b) these excipients are present in amounts normally used in IR solid oral dosage forms, (c) the test product is very rapidly dissolving, (d) the SmPC of the test product indicates the need for monitoring of the patient's liver function.


Assuntos
Antituberculosos , Pirazinamida , Comprimidos , Administração Oral , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Disponibilidade Biológica , Excipientes , Humanos , Pirazinamida/administração & dosagem , Pirazinamida/efeitos adversos , Pirazinamida/farmacocinética , Pirazinamida/farmacologia , Solubilidade , Equivalência Terapêutica
14.
J Pharm Sci ; 97(9): 3700-8, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18271037

RESUMO

Literature data are reviewed relevant to the decision for a biowaiver of immediate release (IR) solid oral dosage forms containing metoclopramide hydrochloride. In addition, new solubility data, obtained under Biopharmaceutics Classification System (BCS) conditions are presented. Metoclopramide HCl is conservatively assigned to BCS Class III. Taken also into consideration excipient interactions reported in metoclopramide drug products, its pharmacokinetic properties and therapeutic use and therapeutic index, a biowaiver can be recommended when: (a) the test product contains only excipients present also in metoclopramide HCl containing IR solid oral drug products approved in ICH or associated countries, for instance as presented in this paper, (b) in amounts in normal use in IR solid oral dosage forms, and (c) the test product and the comparator both comply with the criteria for very rapidly dissolving.


Assuntos
Antieméticos , Antagonistas de Dopamina , Metoclopramida , Comprimidos , Administração Oral , Antieméticos/administração & dosagem , Antieméticos/farmacocinética , Antieméticos/farmacologia , Disponibilidade Biológica , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacocinética , Antagonistas de Dopamina/farmacologia , Excipientes , Humanos , Metoclopramida/administração & dosagem , Metoclopramida/farmacocinética , Metoclopramida/farmacologia , Solubilidade
15.
Int J Pharm ; 355(1-2): 299-306, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18206322

RESUMO

TMC and DEMC, quaternized derivatives of chitosan, have been shown to have penetration enhancement properties and able to open the tight junctions of the intestinal epithelia at neutral and alkaline pH environments. The use of the nanoparticulate systems has the advantage of protecting the peptidic drugs from the harsh environment of the gastrointestinal tract. Hence, the aim of this study was to synthesize and characterize TMC and DEMC, both with quaternization degrees of 50+/-5%, which were then used to prepare insulin nanoparticles with two different methods: ionotropic gelation and the polyelectrolyte complexation (PEC) techniques. The obtained nanoparticles were then characterized for size, zeta potential, insulin loading and release as well as antibacterial activities. The results showed that nanoparticles prepared by the PEC method had higher insulin loading efficiency and zeta potential than those made by the ionotropic gelation method and may subsequently be used for further in vitro, ex vivo and in vivo studies. Moreover, the antibacterial studies suggest that the polymers in free form have higher antibacterial activity against Gram-positive bacteria than in the nanoparticulate form.


Assuntos
Quitosana/análogos & derivados , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Nanopartículas/química , Quitosana/química , Quitosana/farmacologia , Estabilidade de Medicamentos , Eletroquímica , Eletrólitos , Excipientes , Géis , Hipoglicemiantes/química , Insulina/química , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Solubilidade , Staphylococcus aureus/efeitos dos fármacos
16.
J Pharm Sci ; 97(4): 1350-60, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17879380

RESUMO

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing ethambutol dihydrochloride as the only active pharmaceutical ingredient (API) are reviewed. Ethambutol dihydrochloride is a Biopharmaceutics Classification System (BCS) Class III drug with permeability properties approaching the border between BCS Class I and III. BE problems of ethambutol formulations containing different excipients and different dosages forms have not been reported and hence the risk of bioinequivalence caused by excipients is low. Ethambutol has a narrow therapeutic index related to ocular toxicity. However, as long as the prescribers' information of the test product stipulates the need for regular monitoring of ocular toxicity, the additional patient risk is deemed acceptable. It is concluded that a biowaiver can be recommended for IR solid oral dosage forms provided that the test product (a) contains only excipients present in ethambutol IR solid oral drug products approved in ICH or associated countries, for instance as presented in this paper, (b) complies with the criteria for "very rapidly dissolving" and (c) has a prescribers' information indicating the need for testing the patient's vision prior to initiating ethambutol therapy and regularly during therapy.


Assuntos
Etambutol/administração & dosagem , Absorção , Administração Oral , Células CACO-2 , Etambutol/química , Etambutol/farmacocinética , Excipientes , Humanos , Permeabilidade , Solubilidade , Equivalência Terapêutica
17.
J Pharm Sci ; 96(6): 1480-9, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17387693

RESUMO

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisone are reviewed. Due to insufficient data prednisone cannot be definitively classified according to the current Biopharmaceutics Classification System (BCS) criteria as both the solubility and the permeability of prednisone are on the borderline of the present criteria of BCS Class I. Prednisone's therapeutic indications and therapeutic index, pharmacokinetics and the possibility of excipient interactions were also taken into consideration. Available evidence indicates that a biowaiver for IR solid oral dosage forms formulated with the excipients tabulated in this article would be unlikely to expose patients to undue risks.


Assuntos
Prednisona/farmacocinética , Administração Oral , Excipientes/administração & dosagem , Humanos , Permeabilidade , Prednisona/administração & dosagem , Prednisona/química , Solubilidade , Equivalência Terapêutica
18.
J Pharm Sci ; 96(1): 27-37, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17039494

RESUMO

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisolone are reviewed. Data on its solubility, oral absorption, and permeability are not totally conclusive, but strongly suggest a BCS Class 1 classification. Prednisolone's therapeutic indications and therapeutic index, pharmacokinetics, and the possibility of excipient interactions were also taken into consideration. Available evidence indicates that a biowaiver for IR solid oral dosage forms formulated with the excipients tabulated in this article would be unlikely to expose patients to undue risks.


Assuntos
Anti-Inflamatórios/farmacocinética , Prednisolona/farmacocinética , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/química , Disponibilidade Biológica , Biofarmácia , Química Farmacêutica , Ensaios Clínicos como Assunto , Formas de Dosagem , Aprovação de Drogas , Excipientes/química , Humanos , Absorção Intestinal , Permeabilidade , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Prednisolona/química , Medição de Risco , Solubilidade , Equivalência Terapêutica
19.
J Pharm Sci ; 96(3): 522-31, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17117431

RESUMO

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing isoniazid as the only active pharmaceutical ingredient (API) are reviewed. Isoniazid's solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. Isoniazid is "highly soluble" but data on its oral absorption and permeability are inconclusive, suggesting this API to be on the borderline of BCS Class I and III. For a number of excipients, an interaction with the permeability is extreme unlikely, but lactose and other deoxidizing saccharides can form condensation products with isoniazid, which may be less permeable than the free API. A biowaiver is recommended for IR solid oral drug products containing isoniazid as the sole API, provided that the test product meets the WHO requirements for "very rapidly dissolving" and contains only the excipients commonly used in isoniazid products, as listed in this article. Lactose and/or other deoxidizing saccharides containing formulations should be subjected to an in vivo BE study.


Assuntos
Isoniazida/administração & dosagem , Disponibilidade Biológica , Excipientes , Humanos , Absorção Intestinal , Isoniazida/química , Isoniazida/farmacocinética , Permeabilidade , Solubilidade , Equivalência Terapêutica
20.
J Pharm Sci ; 95(5): 974-84, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16557528

RESUMO

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing cimetidine are reviewed. According to the current Biopharmaceutics Classification System (BCS), cimetidine would be assigned to Class III. Cimetidine's therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability (BA) problems were also taken into consideration. On the basis of the overall evidence, a biowaiver can be recommended for cimetidine IR products, provided that the test product contains only those excipients reported in this paper in their usual amounts, and that the test and the comparator drug products both are "rapidly dissolving" as per BCS.


Assuntos
Cimetidina/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Fenômenos Químicos , Físico-Química , Cimetidina/farmacocinética , Formas de Dosagem , Ésteres , Excipientes , Antagonistas dos Receptores H2 da Histamina/farmacocinética , Humanos , Isomerismo , Permeabilidade , Ratos , Sais , Solubilidade , Equivalência Terapêutica , Distribuição Tecidual
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