Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (bcs) literature data: chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride

Biowaiver Monographs for Immediate Release Solid OralDosage Forms Based on Biopharmaceutics ClassificationSystem (BCS) Literature Data: Chloroquine Phosphate,Chloroquine Sulfate, and Chloroquine Hydrochloride R.K. VERBEECK,1 H.E. JUNGINGER,2 K.K. MIDHA,3 V.P. SHAH,4 D.M. BARENDS5 1Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa 2Leiden/Amsterdam Center for Drug Research, Leiden University, Division of Pharmaceutical Technology,Leiden, The Netherlands 3University of Saskatchewan, Saskatoon, Saskatchewan, Canada 4Center of Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland 5RIVM—National Institute for Public Health and the Environment, Laboratory for Quality Control of Medicines,P.O. Box 1, 3720 BA Bilthoven, The Netherlands Received 19 July 2004; revised 29 November 2004; accepted 20 January 2005 Published online in Wiley InterScience ( DOI 10.1002/jps.20343 ABSTRACT: Literature data on the properties of chloroquine phosphate, chloroquinesulfate, and chloroquine hydrochloride related to the Biopharmaceutics ClassificationSystem (BCS) are reviewed. The available information indicates that these chloroquinesalts can be classified as highly soluble and highly permeable, i.e., BCS class I.
The qualitative composition of immediate release (IR) tablets containing these ActivePharmaceutical Ingredients (APIs) with a Marketing Authorization (MA) in Belgium(BE), Germany (DE), Finland (FI), and The Netherlands (NL) is provided. In view ofthese MA's and the critical therapeutic indication of chloroquine, it is assumed that theregistration authorities had evidence that these formulations are bioequivalent tothe innovator. It is concluded that IR tablets formulated with these excipients arecandidates for a biowaiver. ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association JPharm Sci 94:1389–1395, 2005Keywords: absorption; BCS; chloroquine; permeability; solubility therapeutic use, concerning their propertiesrelated to the Biopharmaceutics Classification A monograph based on literature data is pre- System (BCS). Purpose and scope of these mono- sented on the three salt forms of chloroquine in graphs were discussed previously.1 The workingprocedure was identical as described earlier.1 Theobjectives of these monographs are to evaluate all This study reflects the scientific opinion of the authors and data from various literature sources and to come not the policies of regulating agencies.
to a conclusion whether or not to recommend a Correspondence to: D.M. Barends (Telephone: þ31 30 biowaiver for immediate release (IR) solid oral 2744209; Fax: þ31 30 2744462; E-mail: [email protected]) dosage forms containing one of the water-soluble Journal of Pharmaceutical Sciences, Vol. 94, 1389–1395 (2005)ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association chloroquine salts.
GENERAL CHARACTERISTICS CHEMICAL PROPERTIES Choroquine Phosphate sesses an asymmetric carbon atom and thereforeexists as two enantiomers, S(þ)-chloroquine and R()-chloroquine.2 Its structure is shown in water.3,5,6 An aqueous solubility of 1 in 4 was Figure 1. Only preparations containing the reported.7 It is not clear if this means 1 part racemic mixture are commercially available. In dissolved in 4 part solution, i.e., 250 mg/ml, or 1 this monograph, chloroquine is understood to be part dissolvable in 4 parts of water, i.e., 200 mg/ the racemic form, unless otherwise indicated.
ml. Other workers reported a solubility of 100 mg/ Only salts are normally used: the diphosphate (usually called chloroquine phosphate), the sul-fate, and hydrochloride.3 For the phosphate, the Chloroquine Sulfate sulfate and the hydrochloride, 100 mg chloro- Chloroquine sulfate is freely soluble in water.3,5 quine base is equivalent to 161, 136, and 123 mg Other workers reported an aqueous solubility of of these salts, respectively.3 The wording chlor- 1 in 3, i.e., 250 or 333 mg/ml, see above.7 oquine is used to describe attributes that all threesubstances have in common, otherwise the spe- cific salt is mentioned.
No literature data were found.
Therapeutic Indication Chloroquine is used in the treatment and pro- Chloroquine phosphate exists in two polymorphic phylaxis of malaria and has also been used in forms which have melting points at approxi- the treatment of hepatic amoebiasis, lupus mately 195 and 2188C.6 erythematosus, and light-sensitive skin erup-tions.3 Chloroquine possesses anti-inflammatory Partition Coefficient properties and rheumatoid arthritis is a further For the uncharged chloroquine base, a log P (n- indication for this drug.3,4 Frequent Adverse octanol/water) of 3.73 was reported, this value Drug Reactions (ADRs) of chloroquine include being calculated using a fragmentation method based on atomic contributions to lipophilicity.8 and gastrointestinal (GI) disturbances such as ClogP, calculated by using the ClogP program nausea, vomiting, and diarrhea.3 More rarely, (version 3.0, Biobyte Corp., Clalement, CA, http:// mental changes including psychotic episodes, was 5.06.8 Augustijns mea- agitation, and personality changes may occur.3 sured partitioning of chloroquine in octanol/ Retinopathy is a severe ADR of chloroquine transport medium pH 7.2 at different tempera- and can result in visual impairment.3 Acute tures.9 The logarithm of the distribution coeffi- cient, log D, at pH 7.2 and 378C was 0.83.
dangerous and death can occur within a fewhours.3 Chloroquine possesses two basic ionization sites.
pKa values of 8.1 and 10.4 at 378C and 8.4 and10.8 at 208C, respectively, were reported.2,10Other workers reported values of 8.10 and 9.94without referring to temperature.6 Available Dose/Tablet The usual tablet strength is the equivalent of100 mg chloroquine base.3 The dose recommendby the WHO for tablets is 150 mg base (asphosphate or sulfate).11 Structure of chloroquine.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 7, JULY 2005 BIOWAIVER MONOGRAPH FOR CHLOROQUINE The pharmacokinetics of chloroquine have been reviewed.15,17 Chloroquine is bound to an extent Augustijns studied the transport of chloroquine of 60% to plasma proteins.21,22 Chloroquine is phosphate in Caco-2 cell monolayers and con- much more extensively bound to various body cluded that chloroquine crosses the intestinal tissues, including the cellular components of epithelium by passive diffusion.9 Apparent per- blood.23,24 The combination of moderate plasma meability coefficients (Papp) reported are 2.3  protein binding and extensive binding to tissues 106 and 20.0  106 cm/s at pH 6.0 and 7.2, explains its extremely large distribution volume respectively.9 However, these data were obtained of 200–800 L/kg.15,17 The total body clearance of without establishing an in-house correlation chloroquine is approximately 0.10 L/h/kg based on between Papp and the fraction dose absorbed (fa) whole blood concentrations, and 0.7–1.0 L/h/kg for a set of model drugs.12,13 Also, no internal based on plasma concentrations.15,17 The long standards as proposed by the FDA Biowaiver terminal plasma half-life of chloroquine, ranging guideline were used.14 from 20 to 60 days, is due to its large distributionvolume. The pharmacokinetics of chloroquinewere shown to be linear following administration of single oral doses between 2 and 15 mg/kgchloroquine base.25 Chloroquine is rapidly and almost completelyabsorbed from the gastro-intestinal (GI) tractwhen given orally.15 The average oral bioavailab- Metabolism and Excretion lity (BA) is approximately 89%.16 However, the intersubject variability in chloroquine absorption equally to the elimination of chloroquine: approxi- is high; oral BA values between 67% and 114% mately 40%–50% of the administered dose has have been reported.15,17 The oral BA of chloro- been reported to be excreted unchanged in the quine was significantly reduced, by more than urine in individuals with normal renal function.24 60% i.e., to 40%, in malnourished children.18 Chloroquine is rapidly dealkylated to the phar- The absorption of chloroquine is increased macologically active N-desethylchloroquine, bis- when taken with food.3 For example, following administration of an oral dose with a standard inoline.15,17,26 Additional metabolites, such as chloroquine N-oxide and chloroquine di-N-oxide (Cmax) and area under the curve (AUC) of chlor- have been detected in plasma and/or urine.
In vitro studies on human liver microsomes have identified CYP2C8, CYP3A4, and CYP2D6 as the main cytochrome P450 isoforms catalyzing In contrast, a significant reduction in BA was the formation of N-desethylchloroquin.27 Augus- observed when chloroquine phosphate was ad- tijns et al.28 studied the pharmacokinetics of both ministered with three common Sudanese be- chloroquine enantiomers and showed moderate, but statistically significant differences in their phosphate with any one of these three beverages terminal elimination half-lives and body clearances.
reduced Cmax and AUC both by approximately The clinical consequences of the stereoselective 70%. All three beverages were fairly acidic pharmacokinetics of R- and S-chloroquine on (pH 2.6–2.8) and the authors postulated that efficacy and toxicity are not known.
the intake of these beverages increased theionization of chloroquine in the GI tract andhence reduced the absorption of chloroquine DOSAGE FORM PERFORMANCE base. Moreover, acidification of the urine bythese beverages may have reduced the tubular reabsorption of chloroquine and consequentlyincreased its renal clearance. The authors sug- The excipients present in IR tablets having a gested that both mechanisms may have contrib- marketing authorization (MA) in Belgium (BE), uted to the observed significant reduction in Germany (DE), Finland (FI), and The Nether- lands (NL) are shown in Table 1. In previous JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 7, JULY 2005 VERBEECK ET AL.
Excipients Present in Chloroquine IR Tablets with a MA in Belgium (BE), Germany (DE), Chloroquine Phosphate Tablets USP 27 are requir- Finland (FI), and The Netherlands (NL) ed to dissolve in the paddle apparatus at 100 rpm not less than 75%(Q) of the labeled amount in45 min in 900 mL water.29 Risha et al.30 evaluated Chloroquine sulfate the quality of the innovator and generic chloro- quine phosphate tablets on the Tanzanian market Magnesium stearate as described in USP 27. In all cases not less than 90% dissolution was observed at 45 min.
Chloroquine phosphate It seems safe to suppose that the solubility of Magnesium stearate the hydrochloride salt is comparable to that of the phosphate and the sulfate and hence these three Pregelatinised starch chloroquine salts are freely soluble in water.
However, solubility data over the full pH range Sodium starch glycollate are lacking. For a biowaiver, the FDA and EMEA guidances require the API to be ‘‘highly soluble'' over the pH range 1.0–7.5 (FDA) or within the range of pH 1–8, preferably at or about pH 1.0, aNivaquine1, SmPC in Belgium.
4.6, and 6.8 (EMEA).14,31 Moreover, when a bNivaquine1, SmPC in The Netherlands, http://www.cbg- biowaiver is granted, comparative dissolution cWeimer1quin/-forte Tabletten. ROTE LISTE1 2004 testing of the test formulation and the reference Arzneimittelsverzeichnis fu¨r Deutschland, ed., Aulendorf formulation is to be carried out at three different Germany: ECV Editio Cantor Verlag,
pH values between 1.0 and 6.8.14,31 The test Heliopar1, SmPC in Finland, formulation has to be ‘‘rapidly dissolving'' in each eChlorochin 250 mg Berlin-Chemie. ROTE LISTE1 2004 of the three media, which is an additional in- Arzneimittelsverzeichnis fu¨r Deutschland, ed., Aulendorf dication that the solubility of the API is suffi- Germany: ECV Editio Cantor Verlag,
fResochin1 junior/Resochin1 Tabletten. ROTE LISTE1 ciently high over the pH-range 1.0–6.8.
2004 Arzneimittelsverzeichnis fu¨r Deutschland, ed., AulendorfGermany: ECV Editio Cantor Verlag,
Absorption and Permeability The permeability data for chloroquine based onCaco-2 experiments are inconclusive because the monographs, such an MA was taken as an method was not validated by using reference indication that this formulation had passed an compounds as proposed by the FDA guidance.9,14 in vivo bioequivalence test.1 However, it appears Caco-2 permeability determinations are known to that this assumption is not so straightforward.
display tremendous inter-laboratory variability In most countries, regulatory authorities have and the use of reference compounds is therefore accepted and do accept small changes in a formu- essential. However, the permeability can also lation without an in vivo bioequivalence study.
be estimated from BA data. The FDA Guidance Therefore, it is not certain that all the formula- defines ‘‘highly permeable'' when the fraction of tions shown in Table 1 have passed an in vivo dose absorbed (fa) is not less than 90%.14 The bioequivalence study. However, in view of the reported BA of chloroquine, which is on average critical therapeutic indication of chloroquine, we 89%, is slightly below that critical limit. It was suppose that the registration authorities of BE, suggested that a limit of 85% might be appro- DE, FI, and NL were in receipt of sufficient priate in defining high permeability.32 Also, evidence to conclude to bioequivalence, even for during a recent workshop consensus was reached formulations that were not actually tested in an that the minimum value of fa can be lowered to in vivo bioequivalence study.
85%.33 The permeability can also be estimated JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 7, JULY 2005 BIOWAIVER MONOGRAPH FOR CHLOROQUINE from the partition coefficient, as was shown by is indicated for serious diseases and very serious Kasim et al.8 In their report, the permeability of ADRs have been reported. The latter, however, 123 substances on the WHO Essential drugs list have been documented in cases of overdose, and was estimated based on correlations of experi- not as a result of relatively minor fluctuations in mentally determined human intestinal perme- plasma concentrations such as those which could abilities of select compounds with log P, ClogP, or be seen in case of bioinequivalence.
log D values.8 Substances with a log P, ClogP, or In malaria therapy, resistant parasites are most log D greater than the corresponding values of the likely to be selected if the parasite population is reference substance metoprolol, i.e., 1.72, 1.35, exposed to subtherapeutic drug concentrations.34 and 1.48, respectively, were classified as highly Consequently, assuring the BA of chloroquine permeable. Chloroquine phosphate with values tablets is of utmost importance.
for log P, ClogP, and Log D of 3.73, 5.06, and 0.83,9 Considerations of the therapeutic index and respectively, was therefore classified to be ‘‘highly the pharmacokinetics of chloroquine led in 1998 the German regulatory authorities to catogorize All evidence taken together, it is concluded that chloroquine as an API for which biowaivers could chloroquine is highly permeable.
not be granted.35 Risks of Bioinequivalence Caused by Excipient and/or Manufacturing Conditions The in vitro dissolution test for chloroquine In the tablets which have an MA in several phosphate tablets described in the USP 27 uses European countries, a wide range of excipients is water. This unbuffered medium is very sensitive used. Although, as discussed above, there is no to pH changes. In view of the insolubility of solid proof that all the formulations shown in chloroquine and its salts at alkaline pH-values, a Table 1 have actually passed an in vivo bioequi- buffered medium, with a pH corresponding to the valence study, it can be assumed that the regis- limits of the solubility of chloroquine in water tration authorities had evidence they would be seems to be more discriminating. However, once bioequivalent, if tested in vivo. This suggests that bioequivalence has been established, in vivo or the risk of an excipient effect on the BA of chlo- in vitro, the test USP 27, when applied for batch- roquine for the excipients listed in Table 1 is small to-batch testing, will provide sufficient assurance for the amounts normally present in IR tablets.
of batch-to-batch bioequivalence.
Food interaction itself has no influence on the bioequivalence as long as the BA of the test product and the reference product are influenced to thesame degree, but food interactions can indicate a Although the data do not provide full proof, there potential risk for an excipient interaction. For can be little doubt that neither the solubility, nor instance, the reported reduction of the BA caused the permeability of these salts of chloroquine are by acidic beverages could indicate that there is a limiting factors in the GI absorption. Conse- risk that a test product, containing acidic excipi- quently, they are classified as BCS Class I. Other ents, may be bioinequivalent when the reference workers also classified chloroquine phosphate as product does not contain such excipients. The BCS class I.8,36 This suggests that these chlor- same holds for the reported increase of the BA oquine salts are candidates for a biowaiver.
with food, indicating a potential risk for bio- When considering a biowaiver, difficulties asso- equivalence caused by very lipophilic excipients.
ciated with carrying out in vivo bioequivalence However, the excipients shown in Table 1 are studies with chloroquine is also to be considered.
neither highly acidic nor strongly lipophilic. All Because of its exceptionally long plasma half-life, taken together, it is concluded that for excipients long washout periods are needed. This supports listed in Table 1, used in amounts normally present in IR tablets, the risk of bioinequivalence is small.
The potential consequences of an incorrect biowaiver decision, leading to a bioinequivalent Patient's Risks Associated with Bioinequivalence product, should also be considered. These con- When considering a biowaiver for a drug sub- sequences are serious. However, the risk of bio- stance, its therapeutic index and indication also inequivalence that cannot be detected with need to be taken into account.14,31,32 Chloroquine comparative dissolution testing in pH 1.0. 4.5, JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 7, JULY 2005 VERBEECK ET AL.
and 6.8, is estimated to be very low. This risk is 11. WHO Model List of Essential Medicines 13th edn.
even lower when formulations contain only the Available form URL: excipients shown in Table 1.
We conclude that for chloroquine hydrochloride, 12. Artursson P, Palm K, Luthman K. 2001. Caco-2 chloroquine phosphate, and chloroquine sulfate monolayers in experimental and theoretical predic-tions of drug transport. Adv Drug Deliv Rev 46:27–43.
IR tablets granting a biowaiver is justified for 13. Ungell AL, Karlsson J. 2003. Cell cultures in drug formulations containing the excipients shown discovery: An industrial perspective. In: Water- in Table 1, comply with the requirements for beemd Hvd, Lennerna¨s H, Artursson P, editors.
‘‘rapidly dissolving'' at pH 1.0, pH 4.5, and pH Drug bioavailability: Estimation of solubility, perme- 6.814,31 and also comply with the similarity re- ability, absorption and bioavailability. Weinheim, quirements for comparative dissolution testing Germany: Wiley-VCH. pp 90–131.
versus the reference product at pH 1.0, pH 4.5, 14. US Department of Health and Human Services, Food and Drug Administration, Center for DrugEvaluation and Research (CDER). 2000. Guidancefor industry: Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solidoral dosage forms based on a biopharmaceutics 1. Vogelpoel H, Welink J, Amidon GL, Junginger HE, classification system. Available form URL: http:// Midha KK, Moller H, Olling M, Shah VP, Barends DM. 2004. Biowaiver monographs for immediate 15. Krishna S, White NJ. 1996. Pharmacokinetics of release solid oral dosage forms based on biophar- quinine, chloroquine and amodiaquine. Clinical maceutics classification system (BCS) literature implications. Clin Pharmacokinet 30:263–299.
data: Verapamil hydrochloride, propranolol hydro- 16. Benet LZ, Øie S, Schwartz JB. 1996. Design and chloride, and atenolol. J Pharm Sci 93:1945–1956.
optimization of dosage regimens; pharmacokinetic 2. Tariq M, Al-Badr AA. 1984. Chloroquine. In: Florey data. Goodman & Gilman's The Pharmacolo- K, editor. Analytical profiles of drug substances.
gical Basis of Therapeutics, 9th edn. New York: New York: Academic Press. pp 95–125.
McGraw-Hill. pp 1707–1792.
3. Sweetman S, editor. 2004. Martindale: The com- 17. Ducharme J, Farinotti R. 1996. Clinical pharma- plete drug reference. Electronic version. London cokinetics and metabolism of chloroquine. Focus on UK: Pharmaceutical Press, Thomson MICRO- recent advancements. Clin Pharmacokinet 31:257– MEDEX Healthcare Series Vol. 123, expires 3/ 2005, Greenwood Village, Colorado.
18. Walker O, Dawodu AH, Salako LA, Alvan G, 4. Furst DE. 1996. Pharmacokinetics of hydroxychlor- Johnson AO. 1987. Single dose disposition of chloro- oquine and chloroquine during treatment of rheu- quine in kwashiorkor and normal children— matic diseases. Lupus 5:S11–S15.
Evidence for decreased absorption in kwashiorkor.
5. European Pharmacopoeia, 4th edn. Strasbourg, Br J Clin Pharmacol 23:467–472.
France: Council of Europe, European Directorate 19. Tulpule A, Krishnaswamy K. 1982. Effect of food on for the Quality of Medicines.
bioavailability of chloroquine. Eur J Clin Pharma- 6. Hong DD. 1976. Chloroquine phosphate. In: Florey col 23:271–273.
K, editor. Analytical profiles of drug substances.
20. Mahmoud BM, Ali HM, Homeida MM, Bennett JL.
New York: Academic Press. pp 61–85.
1994. Significant reduction in chloroquine bio- 7. Moffat AC, Jackson JV, Moss MS, Widdop B, editors.
availability following coadministration with the 1986. Clarke's isolation and identification of drugs, Sudanese beverages Aradaib, Karkadi and Lemon.
2nd edn. London UK: The Pharmaceutical Press.
J Antimicrob Chemother 33:1005–1009.
8. Kasim NA, Whitehouse M, Ramachandran C, 21. Walker O, Birkett DJ, Alvan G, Gustafsson LL, Bermejo M, Lennerna¨s H, Hussain AS, Junginger Sjoqvist F. 1983. Characterization of chloroquine HE, Stavchansky SA, Midha KK, Shah VP, Amidon plasma protein binding in man. Br J Clin Pharma- GL. 2004. Molecular properties of WHO essential col 15:375–377.
drugs and provisional biopharmaceutical classifica- 22. Ofori-Adjei D, Ericsson O, Lindstrom B, Sjoqvist F.
tion. Mol Pharm 1:85–96.
1986. Protein binding of chloroquine enantiomers 9. Augustijns PF. 1996. Uptake and transport char- and desethylchloroquine. Br J Clin Pharmacol acteristics of chloroquine in an in vitro cell culture system of the intestinal mucosa, Caco-2. J Pharm 23. Ferrari V, Cutler DJ. 1990. Uptake of chloroquine by human erythrocytes. Biochem Pharmacol 39: 10. Ferrari V, Cutler DJ. 1987. Temperature depen- dence of the acid dissociation constants of chlor- 24. Gustafsson LL, Walker O, Alvan G, Beermann B, oquine. J Pharm Sci 76:554–556.
Estevez F, Gleisner L, Lindstrom B, Sjoqvist F.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 7, JULY 2005 BIOWAIVER MONOGRAPH FOR CHLOROQUINE 1983. Disposition of chloroquine in man after single intravenous and oral doses. Br J Clin Pharmacol 32. Yu LX, Amidon GL, Polli JE, Zhao H, Mehta MU, 25. Gustafsson LL, Rombo L, Alvan G, Bjorkman A, Conner DP, Shah VP, Lesko LJ, Chen ML, Lee VH, Lind M, Walker O. 1983. On the question of dose- Hussain AS. 2002. Biopharmaceutics classification dependent chloroquine elimination of a single oral system: the scientific basis for biowaiver exten- dose. Clin Pharmacol Ther 34:383–385.
sions. Pharm Res 19:921–925.
26. Ette EI, Essien EE, Thomas WO, Brown-Awala EA.
33. Polli JE, Yu LX, Cook JA, Amidon GL, Borchardt 1989. Pharmacokinetics of chloroquine and some of RT, Burnside BA, Burton PS, Chen ML, Conner its metabolites in healthy volunteers: A single dose DP, Faustino PJ, Hawi AA, Hussain AS, Joshi HN, study. J Clin Pharmacol 29:457–462.
Kwei G, Lee VH, Lesko LJ, Lipper RA, Loper AE, 27. Projean D, Baune B, Farinotti R, Flinois JP, Nerurkar SG, Polli JW, Sanvordeker DR, Taneja R, Beaune P, Taburet AM, Ducharme J. 2003. In vitro Uppoor RS, Vattikonda CS, Wilding I, Zhang G.
2004. Summary workshop report: Biopharmaceu- CYP2C8, CYP3A4, and CYP2D6 as the main tics classification system—Implementation chal- isoforms catalyzing N-desethylchloroquine forma- lenges and extension opportunities. J Pharm Sci tion. Drug Metab Dispos 31:748–754.
28. Augustijns P, Verbeke N. 1993. Stereoselective 34. McKeage K, Scott L. 2003. Atovaquone/proguanil: pharmacokinetic properties of chloroquine and de- A review of its use for the prophylaxis of Plasmo- ethyl-chloroquine in humans. Clin Pharmacokinet dium falciparum malaria. Drugs 63:597–623.
35. Gleiter CH, Klotz U, Kuhlmann J, Blume H, 29. USP 27-NF 22. 2004. The United States Pharma- Stanislaus F, Harder S, Paulus H, Poethko-Muller copeia—The National Formulary. Rockville, MD: C, Holz-Slomczyk M. 1998. When are bioavailabil- The United States Pharmacopeial Convention, Inc.
ity studies required? A German proposal. J Clin 30. Risha PG, Shewiyo D, Msami A, Masuki G, Vergote G, Vervaet C, Remon JP. 2002. In vitro evaluation 36. Lindenberg M, Kopp S, Dressman JB. 2004.
of the quality of essential drugs on the Tanzanian Classification of orally administered drugs on the market. Trop Med Int Health 7:701–707.
World Health Organization Model list of Essential 31. Committee for Proprietary Medicinal Products (CPMP). 2001. Note for Guidance on the Investiga- classification system. Eur J Pharm Biopharm 58: tion of Bioavailability and Bioequivalence. Avail- JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 7, JULY 2005


Paradigm w05

Illinois Institute Institute Addiction at Proctor Hospital Young Adolescents Journey to Recovery Leave Well Enough Alone Helping People Change: Make or Break Denial Humility — The Key NON PROFIT U.S. POSTAGE PERMIT NO. 135 MIDLAND, MI 48640 Table of Contents Winter 2005 Rick Zehr, M.S., C.S.A.D.C., P.C.G.C., MISA IIMedical Directors:

Redalyc. patrones de autoatención y automedicación entre la población estudiantil universitaria de la ciudad de puebla . elementos: ciencia y cultura

Elementos: ciencia y culturaBenemérita Universidad Autónoma de PueblaISSN: 0187-9073 MÉXICO Enrique Soto Pérez de Celis / Yolanda Roa Nava PATRONES DE AUTOATENCIÓN Y AUTOMEDICACIÓN ENTRE LA POBLACIÓN ESTUDIANTIL UNIVERSITARIA DE LA CIUDAD DE PUEBLA Elementos: ciencia y cultura, octubre-diciembre, año/vol. 11, número 055-056 Benemérita Universidad Autónoma de Puebla

Copyright © 2008-2016 No Medical Care