Research Into Paracetamol

Re lookup Into ParacetamolThe pharmaceutical industry was estimated to turnover 773 billion in 2008, fair not on the whole of this revenue was interpreted as profit a signifi orduret cost goes into research and industry guideline shape for produces. With regards to bracing generic medications, proving bioequivalence is crucial to success, stock-still necessary in vivo examen digest be costly ((EMAMI). Drugs which meet a certain Biopharmaceutics Classification establishment criteria may be p whollyiate from these expensive tests and may be permitted a biowaiver (2). This al minuscules in vitro looseness of the bowels testing in place of in vivo plasm analysis. Paracetamol is one much(prenominal) medicine that has qualities which place it at the marginal of biowaiver suitableness (2). It is the worlds around usually delectationd annoying pill (3), although the question arises as to whether all preparations as effective as severally other? More specifically we a sk, is in that respect is whatsoever signifi assholet contrast in the midst of the wastefulness pen of paracetamol generics? This literature review is in preparation of experimental tests designed to acquire if there is any difference in wastefulness profile of viii PBS listed bio combining weight prepararations, and whether this difference may correlate to a clinical significance in much(prenominal) a common place medicate, used by so many.Search St trampgyAll selective information was sourced through earnings databases, i.e. Medline, Pubmed, and Cochrane Library. The search engines Google Scholar and UWA library were in addition utilized. Keywords include. KEY WORDS Paracetamol, acetaminophen, bioequivalent ( healing(predicate)al equivalency), delayed action Preparations, Pharmaceutical Preparations, put backts, Drug Compounding, Chemistry, Pharmaceutical, Observer Variation, Dissolution, Metabolism, In vitro, Drug Content, IVIVC, In vivo, Bioavailability and Co rrelation. erst appropriate articles were sourced, citing and cited articles were to a fault evaluated.ParacetamolHistoryParacetamol (acetaminophen) is one of the worlds most popular do medicatess for the p stretching of pain and fever (3). It was low synthesized in 1878 by Morse, and was used clinically for the first time in 1887 by von Merring (3, 4). Paracetamol fell into obscurity unaw atomic number 18s thereafter in favour of other chemically related drugs much(prenominal)(prenominal) as phenacetin (4). However, phenacetin was subsequent run aground to be nephrotoxic, and the search for a replacement arose (4). In 1950, a accept from Brodie and Axelrod rediscovered paracetamols suitable analgesic properties (3). Although, this drug did not experience unsubtlespread acceptance until the 1970s payable to unfounded concerns about dearty but from then on, it became the most commonly used medication for pain (3). In many countries, such as the United Kingdom, paracetamo l sales carry exceeded those of aspirin since 1980 (3).Physicochemical propertiesParacetamol or N-(4-hydroxyphenyl) acetamide, is a white crystalline powder with a melting point of 168-172C (Martindale). It is slenderly alcohol- oil-soluble in water, ie. one part of paracetamol is soluble in 70 parts of water at room temperature (2). It is too freely soluble in alcohol (Martindale) Paracetamol collections maximal UV submersion at a wavelength of 249nm and is inform to have a pKa of 9.5 at 25C (2).Pharmacology Pharmacokinetics (inc. therapeutic superpower toxicity)Pharmacodynamics Mechanism of ActionThe exact mechanism of action of paracetamol has remained largely abstruse for some time (5-8). For years it has been thought to inhibit the enzyme cyclooxygenase (COX) in a similar manner to non-steroidal anti-inflammatory drugs, until now definitive consequence of analgesia and antipyresis being dependent on COX inhibition is still lack (3). Recently, two independent group s have pissd experimental data that has demonst countd that analgesia involves the potentiation of the cannabinoid vanilloid sapidity in the brain and in the dorsal root ganglia (3). Blockade of cannabinoid (CB1) receptors in rats has eliminated any analgesic properties of paracetamol and suggests that paracetamol is in fact a cannabinomimetic (3).PharmacokineticsAbsorption BioavailabilityParacetamol has been reported to have a bioavailability of 62%-89% in those of a fasted state (2, 7). This expiration from absolute bioavailability is attributed to first pass hepatic metabolism. Peak germ plasm concentrations be reached surrounded by 0.17-2.0 hours post-dosing (9). As judge, food has been shown to reduce assimilation by increase tmax and decreasing Cmax values. Food has not been shown to affect the amount of acetaminophen reaching the blood (2).DistributionParacetamol has a reported volume of distribution of 0.69-1.36L/Kg (10). Around 20%-25% of the drug is bound to plas ma proteins at therapeutic dosages, however this value has been shown to increase to 20%-50% in over dosage. Paracetamol has also been shown to intersect the placenta, and has a 1.24 milk/plasma ratio in nipple milk (2). Paracetamol is an ADEC category A drug, i.e. it is safe to use in pregnancy, as well as breastfeeding (8).Metabolism ExcretionAround 85%-90% of paracetamol is metabolized inwardly the liver via the process of glucuronidation and sulfation (2). These in alive(p) metabolites ar then eliminated by the kidney in the urine. Approximately 5% of paracetamol is passed out unchanged in the urine, the remaining drug is conjugated with cysteine and mercapturic acid (2, 7). The half-life of paracetamol has been reported as 1.9 4.3 hours (2, 7, 9) but lifelong in those with renal impairment.IndicationParacetamol is indicated in the symptomatic treatment of mild-to-mode enumerate pain as well as fever (2, 8) and has also been described to have mild anti-inflammatory proper ties (2).Dose Dosage FormsFor adults, the best single panelling of paracetamol is 1g (2, 8), with a maximum dose of 4g daily (8). Hepatocellular necrosis can continue from doses of 10-15g, and death may result in doses in excess of 20-25g (2). Paracetamol is on tap(predicate) in many dosage forms, as a single sprightly pharmaceutical ingredient (API), or in combination with other analgesics such as codeine (Panadeine), dextropropoxyphene (Di-Gesic), metoclopramide (Metomax), as well as in combination with decongestants such as pseudoephedrine in cold-and-flu preparations (8). This drug is available as immediate hammock (IR) birth control pills, sustained release (SR) tablets, chewable, elixirs, IV injections and suppositories (8).Biopharmaceutics Classification system (subtitles )Drug diarrhoea is an essential component in the assiduousness of any pharmaceutical tabletThe Biopharmaceutics Classification System (BCS) is a method of grouping busy pharmaceutical ingredients (API) base on their solvability and intestinal permeableness (reference? WHO, amidon, FDA, lobenberg, dahan). It al downhearteds for easy denomination of those drugs whose in vivo concentration can be grave anticipated based on their in vitro dissolution. (many amidon) The system relies on the premise that drug dissolution, and thusly solvability, as well as drug permeability are the rate change steps in drug absorption. (amidon, rang + dale, goodman and gilman, dahan, WHO, FDA, lobenberg) This implies that two different products containing the similar drug get out have the very(prenominal) rate and extent of absorption if, over time, they both have the same concentration profile at the intestinal membrane. (amidon) Since it is the dissolution profile of a drug which determines its concentration profile in the intestinal lumen, comparability of this parameter in vitro should produce comparable with(predicate) absorption results in vivo. (amidon) In reality however, only those drugs with risque permeability which are formulated into immediate release (IR) preparations can be easily and reliably applied to this logic (amidon, BW, FDA).There are four physical bodyes within the BCS to which a drug can be assigned (as outlined in figure ?). Class I is comprised of those drugs with high permeability and solubility, these drugs are expected to be well absorbed and, providing dissolution is slower than stomachic emptying, show a good correlational statistics between in vitro dissolution rate and the rate and extent of in vivo absorption (IVIVC) (amidon, FDA, BW). Class II drugs also have high permeability but their solubility is low which ensures in vivo dissolution is the rate limiting step in drug absorption and thus IVIVC is expected (amidon). Class lead drugs have a low permeability with high solubility, traditionally these drugs were believed to have little or no IVIVC (amidon), however recent studies have shown that if a part III drug is very rapidly dissolving then a correlation may exist (Cheng, Jantratid 1). Finally Class IV drugs have both low permeability and solubility these drugs are not expected to show any IVIVC (amidon).Figure ? (http//www.tselinc)For each of the four BCS mobes a drug substance is considered highly soluble when the highest IR dose effectivity is soluble in 250mL or slight of aqueous media over the pH come out of 1-7.5. (FDA) The permeability of a drug is considered high if greater than 90% of a dose is absorbed crosswise the intestinal membrane (FDA, Yu).The genius of the BCS is that it allows easy identification of drug candidates for which comparatively cheap and fast in vitro dissolution testing can transpose the more expensive, time consuming and invasive in vivo absorption testing (emami). The system does away with complex modeling that must account for fasted and supply states as well as cyclical changes in motility and gastric emptying. (amidon, dahan) The impact of the BCS on the pharmaceutical industry was so great that in 2006, creator Dr. Gordon Amidon was awarded the International Pharmaceutical Federation (FIP) Distinguished Scientist Award. (internet reference)Correlation between in vitro dissolution and bioavailabilityFollowing the introduction of the BCS a great comprehend of research was conducted exploring the power of IVIVC. It became a main focus not just of the pharmaceutical industry but also of academia and regulatory administration (emami). IVIVC became popular because it can be used as a substitute for resource intensive bioavailability testing the concept has essentially improved the cannonball along and cost of drug development as well as lumber control in pharmaceutical manufacturing (emami).Bioavailability and BioequivalenceBioavailability is an of the essence(p) concept because it determines the efficacy, safety and reproducibility of the therapeutic effect of drugs and the many formulations in which they come (TGA). For the purp ose of drugs that produce a systemic therapeutic effect, the Australian Therapeutic Goods Administration (TGA) (TGA) defines bioavailability as the extent and the rate at which a substance or its active moiety is delivered from a pharmaceutical form and becomes available in the world-wide circulation. Bioavailability is therefore inherently linked to drug absorption and may also be predicted using IVIVC as defined by the BCS.If two pharmaceutically equivalent (same active ingredient and content in the same formulation) products have the same bioavailability they are considered bioequivalent and will essentially have the same efficacy and safety. Bioequivalence is important because it is the basis for which innovator medicines can be substituted with generics.Strength of in vitro in vivo correlationsThe BCS is a predictive tool for determining which drugs will have an IVIVC. circuit card ? demonstrates that under the BCS only sieve II along with some class I drugs are expected to have IVIVCs (amidon). Research subsequent to Dr. Amidons first BCS publication has generally upheld his initial findings however exceptions to the rule have been found.Table ? IVIVC Expectations for Immediate Release Products Based on Biopharmaceutics Class (amidon)Class solubilityPermeabilityIVIVC Expectation*IHighHighIVIVC if dissolution rate is slower than gastric emptying rate, otherwise limit or no correlationII let outHighIVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate, unless dose is very highIIIHighLowAbsorption (permeability) is rate determining and check or no IVIVC with dissolution rateIVLowLowLimited or no IVIVC expected*A limited correlation means that the dissolution rate while not controlling may be similar to the absorption rate and the extent of correlation will depend on the relative rates.Drugs with IVIVCThe BCS suggests that if the bioavailability of a drug is dissolution rate limited then a good IVIVC should be possible. Thi s notion has been present for flutamide a very poorly soluble high dose deepen which is not expected to have IVIVC but has dissolution rate limited absorption (posti). A paper published by Posti, Katila Kostiainen(posti) concluded that there is a laborious IVIVC for flutamide and this was identified on four separate cause where bioavailability was studied. All four studies were of single dose, cross over design and each subsequent landing field increased the number of subjects tested ( consume I n = 6, Study IV n = 24). The strength of the papers methodology provides good support for its conclusions however this was undermined by a lack of documented statistical analysis.Much more compelling evidence comes from a study by Sakuma et. al. (Sakuma) which was able to show an IVIVC for two BCS class I drugs after they standard an enteral coating, thus eliminating the possibility that gastric emptying was the rate limiting step. The results were statistically significant however t he tablets were tested in rat models alternatively than human subjects and the dissolution test may not have adequately reflected the in vivo environment that enteric coated tablets are subject to (Sakuma). make headway study in human subjects demonstrating the difference in IVIVC between enteric and non-enteric coated tablets could not be identified in the literature.There are hundreds of other drugs which have an IVIVC and these are neither limited to BCS class II drugs or drugs with dissolution rate limited absorption. Theophylline is a BCS class IV drug and yet in a complete cross over study of four different theophylline tablets the in vitro dissolution was able to significantly predict several in vivo pharmacokinetic parameters (AUC Cmax) which dictate bioavailability (varshosaz). The study was small (n = 6) and not all pharmacokinetic parameters could be correlated. Other common drug examples with IVIVC include digoxin (shaw), rifampicin (pahkla), diclofenac (Jantratid 2) and lamotrigine (hiten) and these are by no means exhaustive.Drugs without IVIVCnot all drugs have an IVIVC and this can also include some BCS class II drugs. A research paper by Frick, Moller Wirbitzki 1998(frick) demonstrated that the in vitro dissolution of glimepiride (BCS class II) is not comparable to dissolution in vivo. The study employed a single dose cross-over design with 12 subjects, latin-square statistical analysis was employed and the results are assumed to be significant however not all the data was accompanied by supporting assumption values. No correlation was possible because the solubility of glimepiride is low and strongly pH dependent (frick).Unlike glimepiride ciprofloxacin, a quinolone antibiotic, is separate as a BCS class III drug and as a consequence would not be predicted to have an IVIVC. Correspondingly, when tested for this possibility none could be found between dissolution and any of the parameters for bioavalabilty (Tmax, Cmax, AUC Ka) (khan).S trength of BCS in predicting IVIVCThere is a wide variance between IVIVCs that are anticipated according to the BCS and those that are in truth demonstrated after experimental testing. Examples have been provided where both expected and unforeseen correlation occurs and this suggests that the BCS system while helpful should only be taken as a guide. Laboratory testing is still the only received method for determining if a correlation is occurs. Paracetamol is a BCS class III medication and as such is not expected to demonstrate strong IVIVC. Given the fact that paracetamol has a wide therapeutic advocate and the BCS can only be used as a guide, a safe and useable IVIVC may still exist.IVIVC of paracetamolThe prodigious use of paracetamol, vast quantities of the drug manufactured and the presence of many generic products in the marketplace makes it a prime candidate for IVIVC testing. In 1996 Retaco et. al.(retaco) conducted a small crossover study using five subjects to assess wh ether an IVIVC for paracetamol may exist. The study stated that the absorption data from saliva partially correlated with those found in vitro(retaco), however this is not a valid conclusion. One of the subjects studied produced in vivo data that opposed a correlation and this anomaly was further compounded by the fact that statistical analysis was not performed on the IVIVC but rather covered the in vitro and in vivo data separately. This pilot study was later verifiedretaco (word document)invivo bioequivalence but not invitro dissolution equivalentBabalola (word document)Cautious use of IVIVCDominguezIVIVC but not bioequivalentDont use IVIVCBiowaiver for bioequivalence testingIn vivo bioequivalence studies are postulate to ascertain the risk of therapeutic inequivalence from potential differences in bioavailability. The BCS has outlined properties of significant preparations which require evaluation, i.e. solubility, permeability, and dissolution rate (11). In addition to this, the non-critical therapeutic range of a drug should also be considered (11). It should be noted that products produced by the same manufacturer at the same site are exempt from bioequivalence studies (12).ParacetamolBCS classification germane(predicate) properties.Several characteristics must be considered when a drug presents as a candidate for a biowaiver through dissolution testing. Paracetamol is classified as a BCS Class III drug, although it possesses properties which deem it to be borderline Class I (2).Characteristics relevant to the active ingredient Risk of therapeutic failure or adverse drug reactions i.e. the need for critical plasma concentrations. When considering a biowaiver for a drug substance, its therapeutic use and therapeutic index also needs to be taken into account (13). In the skid of paracetamol, the therapeutic indications are not critical, and there is a wide difference between the usual therapeutic dose and toxic doses. Given that an optimal therapeut ic dose for an adult is 1g, and that hepatocellular necrosis can result from uptake of 10-15g, it can be assumed that acetaminophen is not a pin up therapeutic index drug (2).Risk of bioinequivalence Previous evidence of bioavailability problems for an active substance can complicate the justification of in vitro dissolution bioequivalence correlation (11). For paracetamol, the absolute bioavailability has not been shown to vary between therapeutic dose ranges of 5-20mg/kg (2). Other studies have also demonstrated that bioequivalence in different IR paracetamol preparations is achievable (10, 14, 15).Solubility If a drug is highly water soluble it generally lends to exemption of bioequivalence testing, however polymorphism and particle size are major determinants of dissolution and must be considered (11). A drug is considered highly soluble if the amount contained in a preparation of maximal strength fragments in 250mL of three buffered solutions ranging between a pH of 1-8 at 37C (11). Paracetamol has a pKa of 9.5 and is therefore not substantially ionized at a pH less than 9. As a result, it can be said that its solubility does not vary with pH (2). The highest strength IR preparation of paracetamol is 500mg. Experimentally, his has been shown to dissolve in 21mL (2), which is significantly less than the 250mL that is required by the BCS guidances to prove solubility (11, 13).Pharmacokinetic properties High permeability which is typically indicated by a linear absorption pattern, reduces the potential influence of an IR preparation on bioavailability (11). For paracetamol, the permeability is somewhat below the cut-off value of 90%, i.e. one study by Stewart et al. (16) found permeability to be 80% once absorbed. This formally excludes paracetamol from being considered for a biowaiver, although extensions to BCS Class III drugs has recently been given more attention (17, 18).Characteristics relevant to the medicinal product Rapid dissolution Dissoluti on profiles can be regarded as equal when more than 85% of the active ingredient is dissolve within 15 minutes (11). This comparison must occur between test and reference product in three buffers which with a pH range between 1-8, at 37C (11). Paracetamol tablets have been shown to dissolve within 30 minutes (14), however this rate does not satisfy BCS exemption standards.Excipients Those included are to be well established and not in atypically large quantities. Kalantzi et al. (2) details a table of gratifying excipients which can be used within paracetamol IR tablet formulations which are considered for in vitro dissolution biowaiver.Manufacture Critical parameters such as particle size and polymorphism should be addressed and documentation should be provided in the dossier that is submitted to TGA (11). Paracetamol has three metastable forms, the only commercially available from is the monoclinic acetaminophen as it is the most thermodynamically stable polymorph (2).From revie w of the literature, it can be concluded that in vivo bioequivalence testing of solid, oral IR paracetamol dosage forms may not be necessary. This can be justified given that a formulation can be shown to (2)Rapidly dissolve under USP guidelinesContain only the acceptable excipients, in usual quantitiesDemonstrates dissolution profile similar to reference product under conditions stated in USP guidelinesOther drugs with biowaiverOther drugs have been considered for biowaivers, such as acetazolamide, acyclovir, amitryptiline, atenolol, chloroquine, cimetidine, diclofenac, doxycycline hyclate, ethambutol, ibuprofen, isoniazid, metoclopramide, prednisolone, prednisone, pyrazinamide, propranolol, quinidine, ranitidine, rifampicin and verapamil (19). A biowaiver was deemed to be appropriate for all these drugs except for acetazolamide (20) and frusemide (21). Interestingly, both these reviews were performed by the same author.Statement of Purpose signal hypothesisThe purpose of the prop osed study is to compare the dissolution profiles of allegedly bioequivalent IR paracetamol preparations listed on the PBS. In particular, comparisons between every preparation will be made, rather than a single comparison against a referent. We hypothesize that there will be no significant difference between the dissolution profile of IR paracetamol tablets when dissolved according to USP specifications.MethodologyWe propose to poll the dissolution profiles of eight PBS listed bioequivalent paracetamol preparations, namely APO-paracetamol, Chemmart Paracetamol, Dymadon P, Febridol, Panamax, Paracetamol Sandoz, Paralgin, and Terry White Chemists Paracetamol. 16 tablets of each preparation will be dissolved in compliance with USP dissolution test for tablets and capsules, using apparatus II. As mandated, tablets are to be dissolved in 900mL phosphate buffer at a pH of 5.8 with a paddle set to 50rpm. Samples will be taken at intervals of 2,5,10,15,30,45,60 minutes in concordance wit h practice by Dominguez et al. (22). These aliquots will be examined for paracetamol by UV spectrophotometry at 289nm. These data will be statistically analysed by ANOVA.