RESUMO
In preclinical development, salt forms are often screened to assess their ability to improve drug candidate properties. In this study albendazole was used as a model for poorly soluble, weak basic compounds typical of current drug discovery programs. Four salts, the hydrochloride, mesylate, sulfate und tosylate, were prepared and characterized with respect to their physicochemical properties. Identity was confirmed by 1H NMR spectroscopy, ion chromatography and vibrational spectroscopy. The solid state forms of the albendazole salts were examined by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), laser diffraction measurement of particle size distribution (PSD), B.E.T. measurement of the specific surface area and 13C solid state NMR spectroscopy. Thermal behaviour and hygroscopicity were assessed by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), Karl Fischer titration (KFT) and by variable temperature XRPD. Additionally, solubility and dissolution experiments were carried out in water and buffers. The different salt forms show pronounced differences in their physicochemical behaviour, especially with respect to hygroscopicity (sulfate > hydrochloride > tosylate > mesylate) and dissolution (rank order is pH dependent, all better than the free base). A salt form with highly improved physicochemical properties, the mesylate, was identified. The results demonstrate that extensive physicochemical characterization is needed to select the salt form most appropriate for further pharmaceutical development.
Assuntos
Albendazol/química , Anti-Helmínticos/química , Adsorção , Álcalis , Cloretos , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Mesilatos , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Sais , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Sulfatos , Propriedades de Superfície , Termogravimetria , Difração de Raios XRESUMO
The workshop "Drug Permeability - Best Practices for Biopharmaceutics Classification System (BCS) Based Biowaivers" was held virtually on December 6, 2021, organized by the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI), and the Food and Drug Administration (FDA). The workshop focused on the industrial, academic, and regulatory experiences in generating and evaluating permeability data, with the aim to further facilitate implementation of the BCS and efficient development of high-quality drug products globally. As the first international permeability workshop since the BCS based biowaivers was finalized as the ICH M9 guideline, the workshop included lectures, panel discussions, and breakout sessions. Lecture and panel discussion topics covered case studies at IND, NDA, and ANDA stages, typical deficiencies relating to permeability assessment supporting BCS biowaiver, types of evidence that are available to demonstrate high permeability, method suitability of a permeability assay, impact of excipients, importance of global acceptance of permeability methods, opportunities to expand the use of biowaivers (e.g. non-Caco-2 cell lines, totality-of-evidence approach to demonstrate high permeability) and future of permeability testing. Breakout sessions focused on 1) in vitro and in silico intestinal permeability methods; 2) potential excipient effects on permeability and; 3) use of label and literature data to designate permeability class.
Assuntos
Biofarmácia , Relatório de Pesquisa , Preparações Farmacêuticas , Biofarmácia/métodos , Equivalência Terapêutica , Excipientes , Permeabilidade , SolubilidadeRESUMO
The suitability of various media to forecast the solubility of ketoconazole and dipyridamole in the fed stomach at various periods after meal administration was evaluated. Solubilities were measured with the shake-flask method in gastric fluids aspirated 30, 60 and 120 min after administration of 500 ml Ensure plus to healthy fasted adults, in three sets of simulated gastric fluids based on milk, and in simple aqueous buffered media. Simple aqueous buffered media vastly underestimated the intragastric solubility of model compounds in the fed state. When using undigested milk-based media, the solubilities of model compounds in aspirates were also underestimated by a factor of 2.5-27. Solubility in milk digested with pepsin was useful for estimating the intragastric solubility of ketoconazole (within 20%) but overestimated the intragastric values of dipyridamole by a factor of 2-19. For both drugs, the solubility in milk digested with pepsin and lipase predicted the solubility in aspirates collected 60 min after meal administration, whereas at other times it overestimated the intragastric solubility (by a factor of <5). Both the use of biorelevant media and simulation of intragastric digestion are necessary for the prediction of drug solubility in the fed stomach. Milk digested with pepsin and lipase enabled the estimation of the intragastric solubility of dipyridamole and ketoconazole at 1 h after meal intake. Simulation of vesicle/micellar structures seems to be key for the prediction of intragastric solubility in the fed stomach.
Assuntos
Suco Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Preparações Farmacêuticas/metabolismo , Saciação/fisiologia , Adulto , Feminino , Alimentos , Interações Alimento-Droga/fisiologia , Humanos , Masculino , Preparações Farmacêuticas/química , SolubilidadeRESUMO
Early characterization of new drug substances intended for oral application includes not only physicochemical properties and stability but also the ability of the substance to permeate through the intestinal mucosa. In this work, a rapid screening method, surface activity profiling (SAP), is proposed as an alternative to animal studies and screening in cell cultures. Measurements are made with a multichannel tensiometer and require only 50⯵l of stock solution for the complete permeability analysis. Correlation of SAP results with human absorption was demonstrated for marketed drugs and with absorption in rats for development compounds of Boehringer Ingelheim. Cross-laboratory results for marketed drugs showed excellent agreement. For early stage investigations of lead compounds, where only small amounts of the compound are available, the SAP method appears to be an effective and fast tool to accurately predict fa, provided the compound is amphiphilic.
Assuntos
Permeabilidade da Membrana Celular/fisiologia , Absorção Intestinal/fisiologia , Mucosa Intestinal/metabolismo , Animais , Feminino , Humanos , Masculino , Membranas Artificiais , Ratos , Ratos WistarRESUMO
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 TerapêuticaRESUMO
The EU research initiative OrBiTo (oral biopharmaceutics tools) involving partners from academia, pharmaceutical industry, small medium enterprises and a regulatory agency was launched with the goal of improving tools to predict the absorption of drugs in humans and thereby accelerating the formulation development process. The OrBiTo project was divided into four work packages (WP), with WP2 focusing on characterization of drug formulations. The present work introduces the OrBiTo WP2 Decision Tree, which is designed to assist the investigator in choosing the most appropriate in vitro methods for optimizing the oral formulation design and development process. The WP2 Decision Tree consists of four stages to guide the investigator. At the first stage, the investigator is asked to choose the formulation type of interest. At the second stage, the investigator is asked to identify which type of equipment (compendial/modified/noncompendial) is preferred/available. At the third stage, characteristics of the active pharmaceutical ingredient (API) are evaluated and in the fourth stage of the decision tree, suitable experimental protocols are recommended. A link to the living Decision Tree document is provided, and we now invite the pharmaceutical sciences community to apply it to current research and development projects and offer suggestions for improvement and expansion.
Assuntos
Biofarmácia/métodos , Árvores de Decisões , Preparações Farmacêuticas/administração & dosagem , Administração Oral , Desenho de Fármacos , Indústria Farmacêutica/métodos , Liberação Controlada de Fármacos , Humanos , Preparações Farmacêuticas/metabolismoRESUMO
Solubilities measured in water are not always indicative of solubilities in the gastrointestinal tract. The use of aqueous solubility to predict oral drug absorption can therefore lead to very pronounced underestimates of the oral bioavailability, particularly for drugs which are poorly soluble and lipophilic. Mechanisms responsible for enhancing the luminal solubility of such drugs are discussed. Various methods for estimating intra-lumenal solubilities are presented, with emphasis on the two most widely implemented methods: determining solubility in fluids aspirated from the human gastrointestinal tract, and determining solubility in so-called biorelevant media, composed to simulate these fluids. The ability of the biorelevant media to predict solubility in human aspirates and to predict plasma profiles is illustrated with case examples.
Assuntos
Trato Gastrointestinal/metabolismo , Absorção Intestinal , Preparações Farmacêuticas/química , Administração Oral , Animais , Disponibilidade Biológica , Simulação por Computador , Jejum/fisiologia , Humanos , Modelos Biológicos , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , SolubilidadeRESUMO
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 TerapêuticaRESUMO
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 TerapêuticaRESUMO
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 TerapêuticaRESUMO
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 TecidualRESUMO
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 amitriptyline hydrochloride are reviewed. Its therapeutic uses, its pharmacokinetic properties, the possibility of excipient interactions and reported BE/bioavailability (BA) problems are also taken into consideration. Literature data indicates that amitriptyline hydrochloride is a highly permeable active pharmaceutical ingredient (API). Data on the solubility according to the current Biopharmaceutics Classification System (BCS) were not fully available and consequently amitriptyline hydrochloride could not be definitively assigned to either BCS Class I or BCS Class II. But all evidence taken together, a biowaiver can currently be recommended provided that IR tablets are formulated with excipients used in existing approved products and that the dissolution meets the criteria defined in the Guidances.
Assuntos
Amitriptilina/análise , Antidepressivos Tricíclicos/análise , Administração Oral , Amitriptilina/administração & dosagem , Amitriptilina/farmacocinética , Antidepressivos Tricíclicos/administração & dosagem , Antidepressivos Tricíclicos/farmacocinética , Fenômenos Químicos , Físico-Química , Formas de Dosagem , Excipientes , Isomerismo , Permeabilidade , Sais , Solubilidade , Equivalência TerapêuticaRESUMO
Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of absorption. However, some studies show differences in rate of absorption between brands and formulations. In particular, sodium bicarbonate, present in some drug products, was reported to give an increase in the rate of absorption, probably caused by an effect on gastric emptying. In view of Marketing Authorizations (MAs) given in a number of countries to acetaminophen drug products with rapid onset of action, it is concluded that differences in rate of absorption were considered therapeutically not relevant by the Health Authorities. Moreover, in view of its therapeutic use, its wide therapeutic index and its uncomplicated pharmacokinetic properties, in vitro dissolution data collected according to the relevant Guidances can be safely used for declaring bioequivalence (BE) of two acetaminophen formulations. Therefore, accepting a biowaiver for immediate release (IR) acetaminophen solid oral drug products is considered scientifically justified, if the test product contains only those excipients reported in this paper in their usual amounts and the test product is rapidly dissolving, as well as the test product fulfils the criterion of similarity of dissolution profiles to the reference product.
Assuntos
Acetaminofen/farmacocinética , Analgésicos não Narcóticos/farmacocinética , Acetaminofen/administração & dosagem , Acetaminofen/química , Administração Oral , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/química , Disponibilidade Biológica , Química Farmacêutica , Formas de Dosagem , Excipientes , Solubilidade , Equivalência TerapêuticaRESUMO
The regulations with respect to biowaivers for immediate release (IR) solid oral dosage forms in the USA, the EU, Japan and from the World Health Organization (WHO) are summarized and compared. Two case studies are presented, one from our own files and one from the open literature, showing the similarities and the differences among the qualification requirements of the four systems. The regulatory experience gained up to now is reviewed and expected future trends are discussed.
Assuntos
Formas de Dosagem , Controle de Medicamentos e Entorpecentes , Administração Oral , Química Farmacêutica , Solubilidade , Estados Unidos , United States Food and Drug Administration , Organização Mundial da SaúdeRESUMO
Solubility is one of the most important parameters for lead selection and optimization during drug discovery. Its determination should therefore take place as early as possible in the process. Because of the large numbers of compounds involved and the very low amounts of each compound available in the early development stage, it is highly desirable to measure the solubility with as little compound as possible and to be able to improve the throughput of the methods used. In this work, a miniaturized shake-flask method was developed and the solubility results were compared with those measured by semiautomated potentiometric acid/base titrations and computational methods for 21 poorly soluble compounds with solubilities mostly in the range 0.03-30 microg/mL. The potentiometric method is very economical (approximately 100 microg of a poorly soluble compound is needed) and is able to create a pH/solubility profile with one single determination, but is limited to ionizable compounds. The miniaturized shake-flask method can be used for all compounds and a wide variety of media. Its precision and throughput proved superior to the potentiometric method for very poorly soluble compounds. Up to 20 compounds a week can be studied with one set-up. Calculated solubility data seem to be sufficient for a first estimate of the solubility, but they cannot currently be used as a substitute for experimental measurements at key decision points in the development process.
Assuntos
Química Farmacêutica , Preparações Farmacêuticas/química , Potenciometria , Algoritmos , Soluções Tampão , Cromatografia Líquida de Alta Pressão , Composição de Medicamentos , Glibureto/química , Concentração de Íons de Hidrogênio , Redes Neurais de Computação , SolubilidadeRESUMO
Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate release (IR) solid oral dosage forms containing ranitidine hydrochloride are reviewed. According to the current Biopharmaceutics Classification System (BCS), ranitidine hydrochloride should be assigned to Class III. However, based on its therapeutic and therapeutic index, pharmacokinetic properties and data related to the possibility of excipient interactions, a biowaiver can be recommended for IR solid oral dosage forms that are rapidly dissolving and contain only those excipients as reported in this study.
Assuntos
Antagonistas dos Receptores H2 da Histamina/farmacocinética , Ranitidina/farmacocinética , Administração Oral , Biofarmácia , Células CACO-2 , Bases de Dados Bibliográficas , Formas de Dosagem , Aprovação de Drogas , Excipientes , Antagonistas dos Receptores H2 da Histamina/química , Humanos , Permeabilidade , Ranitidina/administração & dosagem , Ranitidina/química , Solubilidade , Equivalência Terapêutica , Fatores de TempoRESUMO
Literature data are reviewed on the properties of ibuprofen related to the biopharmaceutics classification system (BCS). Ibuprofen was assessed to be a BCS class II drug. Differences in composition and/or manufacturing procedures were reported to have an effect on the rate, but not the extent of absorption; such differences are likely to be detectable by comparative in vitro dissolution tests. Also in view of its therapeutic use, its wide therapeutic index and uncomplicated pharmacokinetic properties, a biowaiver for immediate release (IR) ibuprofen solid oral drug products is scientifically justified, provided that the test product contains only those excipients reported in this paper in their usual amounts, the dosage form is rapidly dissolving (85% in 30 min or less) in buffer pH 6.8 and the test product also exhibits similar dissolution profiles to the reference product in buffer pH 1.2, 4.5, and 6.8.
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Biofarmácia/classificação , Ibuprofeno/farmacocinética , Absorção Intestinal , Administração Oral , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Bases de Dados Bibliográficas , Formas de Dosagem , Excipientes/química , Humanos , Concentração de Íons de Hidrogênio , Ibuprofeno/administração & dosagem , Ibuprofeno/química , Ibuprofeno/normas , Solubilidade , Tensoativos/química , Equivalência TerapêuticaRESUMO
Cholylsarcosine (CS) is a semisynthetic bile salt that may be useful in bile salt replacement therapy of short bowel syndrome (SBS). In SBS the bile salt pool becomes depleted, disturbing the uptake of dietary lipids and resulting in weight loss. Previous studies showed that CS in a simple capsule formulation of 1.5-12 g day(-1) can increase the uptake of lipids but often results in gastric irritation. In this work a microgranule dosage form was developed to protect the gastric mucosa while facilitating rapid generation of CS levels in the duodenum. CS microgranules were produced by wet granulation and coated with Eudragit L30D-55 in a fluidized-bed coater. The in-vitro dissolution rate of CS from the microgranules was investigated with USP apparatus under fasted- and fed-state conditions. CS release was delayed under simulated gastric conditions (pH 1.2 and 4.5) but was very fast at higher pH values (5.5, 5.8 and 6.5) more typical of the duodenum. In a pilot clinical trial, four patients received 4 g CS with meals (1.5 g with lunch, 2.5 g with dinner) for 1 week. The parameters investigated were fat absorption coefficient (FAC%), serum beta-carotene level and faecal weight. Although study numbers were too small to achieve statistical significance, the serum beta-carotene level and FAC% increased in the three patients who completed the trial. As expected, the fecal weight did not change. The results indicate that the CS microgranules are promising for the treatment of the intraluminal bile salt deficiency in patients with SBS.
Assuntos
Ácidos Cólicos/administração & dosagem , Ácidos Cólicos/uso terapêutico , Sarcosina/análogos & derivados , Sarcosina/administração & dosagem , Sarcosina/uso terapêutico , Síndrome do Intestino Curto/tratamento farmacológico , Adulto , Química Farmacêutica , Excipientes , Fezes/química , Feminino , Humanos , Concentração de Íons de Hidrogênio , Lipídeos/análise , Microscopia Eletrônica de Varredura , Pessoa de Meia-Idade , Tamanho da Partícula , Projetos Piloto , Ácidos Polimetacrílicos , Pós , Solubilidade , Comprimidos com Revestimento Entérico , beta Caroteno/análiseRESUMO
BACKGROUND: We assessed the efficacy of a high-molecular-weight hydroxypropylmethylcellulose (K8515) as a cholesterol-lowering agent, the dose-response profile of its action, and the ability of adult subjects to tolerate its ingestion at effective doses. METHODS: These studies were conducted at the Clinical Research Center of The University of Michigan Hospitals, Ann Arbor. Efficacy was assessed in 10 normal and 12 mildly hyperlipidemic subjects in double-blind, randomized crossover trials of 1 and 2 weeks' duration, respectively. The dose-response profile was studied in 12 mildly hypercholesterolemic subjects in a nonrandomized control trial with doses given in escalating order. Tolerance was assessed by a questionnaire of adverse effects and bowel movement habits in all subjects. RESULTS: We found that 10 g of K8515 ingested in a prehydrated form three times a day with meals lowered total cholesterol levels by an average of 1.45 mmol/L (56 mg/dL) (32%) in normal subjects within 1 week. In two studies in subjects with mildly elevated cholesterol levels (with entry levels ranging from 5.35 mmol/L [207 mg/dL] to 6.70 mmol/L [260 mg/dL]), average reductions of 1.00 mmol/L (39 mg/dL) (18%) and 1.15 mmol/L (45 mg/dL) (20%) were observed within the same period. The effect was primarily due to a reduction in low-density lipoprotein cholesterol levels. Low-density lipoprotein levels in normal subjects were an average of 1.10 mmol/L (42 mg/dL) (38%) lower after a week of 10 g of K8515 three times a day with meals, and in the two studies in subjects with mild hyperlipidemia, the reductions in low-density lipoprotein levels after 1 week were 0.95 mmol/L (37 mg/dL) (23%) and 1.05 mmol/L (40 mg/dL) (25%). Although there was a tendency for high-density lipoprotein cholesterol levels to decrease, this was significant only in normal subjects. Decreases in cholesterol levels were not accompanied by any rise in triglyceride levels. Dose-response studies in those with mildly elevated cholesterol levels indicated that it is possible to achieve a 15% decrease in low-density lipoprotein cholesterol levels within 1 week at a dose of 6.7 g three times a day, with minimal adverse effects. CONCLUSION: These results suggest a role for high-molecular-weight hydroxypropylmethylcellulose in the clinical treatment of mild hypercholesterolemia.
Assuntos
Anticolesterolemiantes/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Metilcelulose/análogos & derivados , Adulto , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Glicemia/análise , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Defecação , Relação Dose-Resposta a Droga , Método Duplo-Cego , Tolerância a Medicamentos , Fezes , Feminino , Humanos , Hipercolesterolemia/sangue , Derivados da Hipromelose , Masculino , Metilcelulose/administração & dosagem , Metilcelulose/efeitos adversos , Metilcelulose/uso terapêutico , Pessoa de Meia-Idade , Peso Molecular , Placebos , Triglicerídeos/sangueRESUMO
The rate-limiting step to absorption of drugs from the gastrointestinal (GI) tract is often dissolution from the dosage form. Consideration of the Noyes-Whitney dissolution model shows that drug diffusivity, solubility in the gastrointestinal contents, the surface area of the solid wetted by the lumenal fluids and the GI hydrodynamics all play a role in determining the in vivo dissolution rate. Solubility in the GI contents is determined by aqueous solubility, crystalline form, drug lipophilicity, solubilization by native surfactants and co-ingested foodstuffs, and pK(a) in relation to the GI pH profile. Compounds with aqueous solubilities lower than 100 microg/ml often present dissolution limitations to absorption. The dose:solubility ratio of the drug provides an estimate of the volume of fluids required to dissolve an individual dose, and when this volume exceeds 1 l, dissolution is often problematic. The surface area of a drug available for dissolution depends on the particle size of the solid and its ability to be wetted by lumenal fluids. Other physiological factors that can play a role in dissolution include the viscosity of the lumenal contents, through its effect on the diffusivity, and mixing and flow patterns within the gut. In order to better predict in vivo dissolution of drugs, dissolution tests which more adequately simulate the physiological conditions are needed.