The pharmaceutical industry had an estimated turnover of $ 773 billion in 2008, nevertheless non all of this gross was taken as net income; an important cost goes into research and industry guideline conformity. With respect to new generic medicines, turn outing bioequivalence is important to success, nevertheless necessary in vivo testing can be costly. Drugs which meet certain Biopharmaceutics Classification System ( BCS ) standards may be exempt from these expensive trials and can be permitted a biowaiver. This allows in vitro disintegration proving in topographic point of in vivo plasma analysis. Paracetamol is one such drug that has qualities which place it at the boundary line of biowaiver suitability. It is the universe ‘s most normally used analgesic and the inquiry arises as to whether all readings are every bit effectual as each other? More specifically we ask, is there is an important difference between the disintegration profile of paracetamol generics? This literature reappraisal is in readying of experimental trials designed to determine if there is any difference in the disintegration profile of eight bioequivalent readings listed on the Australian Pharmaceutical Benefits Scheme ( PBS ) and whether this difference may correlate to a clinical significance in such a common topographic point drug.
Paracetamol
History
Paracetamol ( Datril ) is one of the universe’s most popular drugs for the intervention of hurting and fever. It was first synthesized in 1878 by Morse and was used clinically for the first clip in 1887 by von Merring. Paracetamol fell into obscureness shortly thenceforth in favor of other chemically related drugs such as phenacetin. However, acetophenetidin was subsequently found to be nephrotoxic, and the hunt for a replacement arose. In 1950, a survey from Brodie and Axelrod rediscovered paracetamol’s suited analgetic properties. Although, this drug did non see widespread credence until the 1970 ‘s due to baseless concerns about safety; but from so on, it became the most normally used pain medicine. In many states, such as the United Kingdom, paracetamol’s gross revenues have exceeded those of aspirin since 1980.
Physicochemical belongings
Paracetamol or N- ( 4-hydroxyphenyl ) ethanamide, is a white crystalline pulverization with a running point of 168-172’C ( Martindale ). It is meagerly soluble in H2O, Internet Explorer. one portion of paracetamol is soluble in 70 parts of H2O at room temperature. It is besides freely soluble in intoxicants. ( Martindale ) Paracetamol shows maximum UV soaking up at a wavelength of 249nm and is reported to hold a pKa of 9.5 at 25’C.
Pharmacology
Pharmacodynamics; Mechanism of Action
The exact mechanism of action of paracetamol has remained mostly unknown for some time. For old ages it has been thought to suppress the enzyme Cox ( COX ) in a similar mode to non-steroidal anti-inflammatory drugs, nevertheless unequivocal cogent evidence of analgesia and antipyresis being dependent on COX suppression is still lacking. Recently, two independent groups have produced experimental information that has demonstrated that analgesia involves the potentiation of the cannabinoid vanilloid tone in the encephalon and the dorsal root ganglia. Blockade of cannabinoid ( CB1 ) receptors in rats have eliminated any analgetic belongings of paracetamol and suggest that paracetamol is cannabinomimetic.
Pharmacokinetics
Absorption; Bioavailability
Paracetamol has been reported to hold a bioavailability of 62 % -89 % in those of a fasted state, this divergence from absolute bioavailability is attributed to first base on balls hepatic metamorphosis. Peak plasma concentrations are reached between 0.17-2.0 hours post-dosing. As expected, the nutrient has been shown to cut down soaking up by increasing tmax and diminishing Cmax values. Food has non been shown to impact the sum of Datril making the blood.
Distribution
Paracetamol has a reported volume of distribution of 0.69-1.36L/Kg. Around 20 % -25 % of the drug is bound to plasma proteins at curative doses; nevertheless, this value has been shown to increase to 20 % -50 % in overdose. Paracetamol has besides been shown to traverse the placenta and has a 1.24 milk/plasma ratio in chest milk. Paracetamol is an ADEC class A drug, i.e. it is safe to utilize in gestation, every bit good as breastfeeding.
Metamorphosis; Elimination
About 85 % -90 % of paracetamol is metabolized within the liver via the procedure of glucuronidation and sulfation. These inactive metabolites are so eliminated by the kidney in the piss. Approximately 5 % of paracetamol is passed out unchanged in the piss, the staying drug is conjugated with cysteine and mercapturic acid. The half-life of paracetamol has been reported as 1.9 – 4.3 hours, but longer in those with nephritic damage.
Indication
Paracetamol is indicated in the diagnostic intervention of mild-to-moderate hurting every bit good as fever and has besides been described to hold mild anti-inflammatory properties.
Dose; Dosage Forms
For grownups, the optimum individual dosage of paracetamol is 1g, with a maximal dosage of 4g daily. Hepatocellular mortification can happen from doses of 10-15g, and decease may ensue in doses in surplus of 20-25g. Paracetamol is available in many dose signifiers, as an individual active pharmaceutical ingredient ( API ), or in combination with other anodynes such as codeine ( Panadeine ) , dextropropoxyphene ( Di-Gesic ) , metoclopramide ( Metomax ) , every bit good as in combination with decongestants such as pseudoephedrine in cold-and-flu preparations. This drug is available as immediate-release ( IR ) tablets, sustained-release ( SR ) tablets, cuttable, elixirs, IV injections, and suppositories.
Biopharmaceutics Categorization System
The Biopharmaceutics Classification System ( BCS ) is a method of grouping active pharmaceutical ingredients ( API ) based on their solubility and enteric permeability. The system allows for easy designation of those drugs whose in vivo soaking up can be easily anticipated based on their in vitro dissolution. This implies that two different merchandise incorporating the same drug will hold the same rate and extent of soaking up if, over clip, they both have the same concentration profile at the enteric membrane. Since it is the disintegration profile of a drug which determines its concentration profile in the enteric LMS, comparison of this parametric quantity in vitro should bring forth comparable soaking up consequences in vivo. In the world nevertheless, merely those drugs with high permeableness which are formulated into IR readings can be easy and faithfully applied to this logic.
BCS Drug Classes
There are four categories within the BCS to which a drug can be assigned ( as outlined in figure 1 ). Class I is comprised of those drugs with high permeableness and solubility, these drugs are expected to be good captives and, supplying disintegration is slower than stomachic voidance, demo a good correlativity between in vitro disintegration rate and the rate and extent of in vivo soaking up ( IVIVC ). Class II drugs besides have high permeableness but their solubility is low which ensures in vivo disintegration is the rate restricting measure in drug soaking up and therefore IVIVC is expected. Class III drugs have a low permeableness with high solubility, traditionally these drugs were believed to hold small or no IVIVC, nevertheless recent surveys have shown that if a category III drug is really quickly fade outing so a correlativity may exist. Finally Class IV drugs have both low permeableness and solubility these drugs are non expected to demo any IVIVC.
For each of the four BCS classes, a drug substance is considered extremely soluble when the highest [ IR ] dose strength is soluble in 250mL or less of aqueous media over the pH scope of 1-7.5. The permeableness of a drug is considered high if greater than 90 % of the dosage is absorbed across the enteric membrane. Using these definitions, paracetamol is classified as a BCS category III drug but it is besides described as marginal category I because it is merely on the cusp of low permeability.
Utility of the BCS
The mastermind of the BCS is that it allows easy designation of drug campaigners for which comparatively inexpensive and fast in vitro disintegration proving can replace the more expensive, clip consuming, and invasive in vivo soaking up testing. The system does off with complex bioavailability mold that must account for fasted and fed provinces every bit good as cyclical alterations in motility and stomachic emptying. The impact of the BCS on the pharmaceutical industry was so great that in 2006, Godhead Dr. Gordon Amidon was awarded the International Pharmaceutical Federation ( FIP ) Distinguished Scientist Award.
Correlation between in vitro disintegration and bioavailability
Following the debut of the BCS, a great trade of research was conducted researching the power of IVIVC. It became a chief focal point non merely of the pharmaceutical industry but besides of academe and regulative authorities. IVIVC became popular because it can be used as a replacement for resource-intensive bioavailability testing; the construct has basically improved the velocity and cost of drug development every bit good as quality control in pharmaceutical manufacturing.
Bioavailability and Bioequivalence
Bioavailability is an of import construct because it determines the efficaciousness, safety, and duplicability of the curative consequence of drugs and the many preparations in which they come. For the intent of drugs that produce a systemic curative consequence, the Australian Therapeutic Goods Administration ( TGA ) 22 defines bioavailability as the extent and the rate at which a substance or its active mediety is delivered from a pharmaceutical signifier and becomes available in the general circulation. Bioavailability is hence inherently linked to drug soaking up and may besides be predicted utilizing IVIVC as defined by the BCS.
If two pharmaceutically tantamount ( same active ingredient and content in the same preparation ) merchandises have the same bioavailability they are considered bioequivalent and will basically hold the same efficaciousness and safety. Bioequivalence is of import because it is the footing for which pioneer medical specialties can be substituted with generics.
Strength of in vitro – in vivo correlatives
The BCS is a prognostic tool for finding which drugs will hold an IVIVC. Table 1 demonstrates that under the BCS merely category II along with some category I drugs are expected to hold IVIVCs. Research subsequent to Dr. Amidon’s first BCS publication has by and large upheld his initial findings nevertheless exclusions to the regulation have been found.
Table 1: IVIVC Expectations for Immediate Release Products Based on Biopharmaceutics Class
| Class | Solubility | Permeability | IVIVC Expectation* |
| 1 | High | High | IVIVC if disintegration rate is slower than stomachic emptying rate, otherwise limited or no correlativity |
| 2 | Low | High |
IVIVC expected if in vitro disintegration rate is similar to in vivo disintegration rate unless the dosage is really high
|
| 3 | High | Low | Absorption ( permeableness ) is rate finding and limited or no IVIVC with disintegration rate |
| 4 | Low | Low | Limited or no IVIVC expected |
*A limited correlativity means that the disintegration rate while non-commanding may be similar to the soaking up rate and the extent of correlativity will depend on the comparative rates.
Drugs with IVIVC
The BCS suggests that if the bioavailability of a drug is dissolution rate limited so a good IVIVC should be possible. This impression has been demonstrated for flutamide a really ill soluble high dosage compound which is non expected to hold IVIVC but has disintegration rate-limited absorption. A paper published by Posti, Katila & A; Kostiainen23 concluded that there is a strong IVIVC for flutamide and this was identified on four separate occasions where bioavailability was studied. All four surveys were of individual dosage, cross-over design and each subsequent survey increased the figure of topics tested ( survey I: n = 6, Study IV: n = 24 ). The strength of the documents methodology provides good support for its decisions nevertheless this was undermined by a deficiency of documented statistical analysis.
Much more compelling grounds come from a survey by Sakuma et. al. which was able to demo an IVIVC for two BCS category I drugs after they received an enteral coating, therefore extinguishing the possibility that stomachic voidance was the rate confining measure. The consequences were statistically important, nevertheless, the tablets were tested in rat theoretical accounts instead of human topics and the disintegration trial may non hold adequately reflect the in vivo environment that enteric-coated tablets are capable to. Further surveys in human topics showing the difference in IVIVC between enteral and non-enteric coated tablets could non be identified in the literature.
There are 100s of other drugs which have an IVIVC and these are neither limited to BCS category II drugs or drugs with disintegration rate-limited soaking up. Theophylline is a BCS category IV drug and yet in a complete cross-over survey of four different Elixophyllin tablets the in vitro disintegration was able to significantly foretell several in vivo pharmacokinetic parametric quantities ( AUC & A; Cmax ) which dictate bioavailability.25 The survey was little ( n = 6 ) and non of all pharmacokinetic parametric quantities could be correlated. Other common drug illustrations with IVIVC include digoxin, rifampicin, diclofenac, and lamotrigine and these are by no agency exhaustive.
Drugs without IVIVC
Not all drugs have an IVIVC and this can besides include some BCS category II drugs. A research paper by Frick, Moller & A; Wirbitzki 199830 demonstrated that the in vitro disintegration of glimepiride ( BCS category II ) is non-comparable to disintegration in vivo. The survey employed an individual dose cross-over design with 12 topics, Latin-Square statistical analysis was employed and the consequences were assumed to be important nevertheless non all the information was accompanied by back using assurance values. No correlativity was possible because the solubility of glimepiride is low and strongly pH-dependent.
Unlike glimepiride, ciprofloxacin a quinolone antibiotic is classified as a BCS category III drug and as an effect would non be predicted to hold an IVIVC. Correspondingly, when tested for this possibility none could be found between disintegration and any of the parametric quantities for bioavailability ( Tmax, Cmax, AUC & A; Ka ).
Strength of BCS in foretelling IVIVC
There is a broad discrepancy between IVIVCs that are anticipated harmonizing to the BCS and those that are really demonstrated after experimental testing. Examples have been provided where both expected and unexpected correlatives occur and this suggests that the BCS system while helpful should merely be taken as an usher. Laboratory testing is still the lone dependable method for finding if a correlativity has occurred. Paracetamol is a BCS category III medicine and as such is non expected to show strong IVIVC. Given the fact that paracetamol has a broad curative index and the BCS can merely be used as an usher, a safe and functional IVIVC may still be.
IVIVC of paracetamol
The colossal usage, huge measures manufactured and the presence of many generic merchandises in the marketplace makes paracetamol a premier campaigner for IVIVC proving. In 1996 Retaco et. al. conducted a little crossing-over survey utilizing five topics to measure whether an IVIVC for paracetamol may be. The survey stated that the soaking up information from “ saliva partly correlated with those found in vitro, this nevertheless is non a valid decision. One of the topics studied produced in vivo information that opposed a correlativity and this anomalousness was further confounded by the fact that statistical analysis was non performed on the IVIVC but instead covered the in vitro and in vivo information individually. This pilot survey was subsequently contradicted by Babalola et. al. who found limited IVIVCs and suggested that paracetamol soaking up may non be limited by its disintegration rate. Similarly, a thorough, good designed, complete crossing over ( 4×4 ) survey that balanced for first-order residuary effects, suggested that it was unsafe to utilize disintegration as the exclusive trial for paracetamol bioequivalence. Interestingly, all of these surveys demonstrated bioequivalence between the assorted merchandise of paracetamol even if they showed no IVIVC.
Biowaiver for bioequivalence testing
In vivo bioequivalence surveys are required to determine the possible differences in bioavailability between pioneer and generic merchandises which, may take to curative inequivalence. A biowaiver provides the authorization and evidence for in fiscal matters intensive bioequivalence proving to be replaced by more tolerable in vitro testing. For the most portion, IVIVC must foremost be established for a drug to be considered for a biowaiver. The BCS has outlined belongings of solid readings which require rating in biowaivers, i.e. solubility, permeableness, and disintegration rate. In add-on to this, the non-critical curative scope of a drug should besides be considered and this is the footing for which paracetamol has gained biowaiver status. It should be noted that merchandises produced by the same maker at the same site are exempt from bioequivalence studies.
Paracetamol
Biowaiver
Several features must be considered when a drug presents as a campaigner for a biowaiver through disintegration testing. Paracetamol is non an authoritative biowaiver campaigner because it is classified as a BCS Class III drug, it does nevertheless possess belongings borderline to Class I3 and these enable it to carry through the demands of a biowaiver.
Biowaiver demands
Features relevant to the active ingredient
Hazard of curative failure or inauspicious drug reactions – i.e. the demand for critical plasma concentrations. When singing a biowaiver for a drug substance, its curative usage and curative index besides need to be taken into account. In the instance of paracetamol, the curative indicants are noncritical, and there is a broad difference between the usual curative dosage and toxic doses. Given that an optimum curative dosage for a grownup is 1g, and that hepatocellular mortification can ensue from consumption of 10-15g, it can be assumed that paracetamol is non a narrow curative index drug.
Hazard of bioequivalence: Previous grounds of bioavailability jobs for an active substance can perplex the justification of in vitro disintegration bioequivalence correlation. For paracetamol, the absolute bioavailability has non been shown to change between curative dose scopes of 5-20mg/kg. Other surveys have besides demonstrated that bioequivalence in different IR paracetamol readings is achievable.
Solubility: If a drug is extremely H2O soluble it by and large lends to freedom of bioequivalence testing, nevertheless polymorphism and atom size are major determiners of disintegration and must be considered. A drug is considered extremely soluble if the sum contained in a readying of maximum strength dissolves in 250mL of three buffered solutions running between a pH of 1-8 at 37’C. Paracetamol has a pKa of 9.5 and is hence non-well ionized at a pH less than 9. As a consequence, it can be said that its solubility does non vary with pH. The highest strength IR readying of paracetamol is 500mg. Experimentally, this has been shown to fade out in 21mL, which is significantly less than the 250mL that is required by the BCS counsel to turn out solubility.
Pharmacokinetic belongings: High permeableness which is typically indicated by an additive soaking up form, reduces the possible influence of an IR readying on bioavailability. For paracetamol, the permeableness is somewhat below the cut-off value of 90 %, i.e. one survey by Stewart et al.38 found permeableness to be 80 % one time absorbed. This officially excludes paracetamol from being considered for a biowaiver, although extensions to BCS Class III drugs have lately been given more attention.
Features relevant to the medicative merchandise
Rapid disintegration: Dissolution profiles can be regarded as equal when more than 85 % of the active ingredient is dissolved within 15 minutes.35 This comparing must happen between trial and mention merchandise in three buffers which with a pH scope between 1-8, at 37’C.35 Paracetamol tablets have been shown to fade out within 30 minutes,32 nevertheless this rate does non fulfill BCS freedom criteria.
Excipients: Those included are to be well established and non in untypically big measures. Kalantzi et al.3 inside pieces of information a tabular array of acceptable excipients which can be used within paracetamol IR tablet preparations which are considered for in vitro disintegration biowaiver.
Industry: Critical parametric quantities such as atom size and polymorphism should be addressed and certification should be provided in the dossier that is submitted to TGA.35 Paracetamol has three metastable signifiers, the merely commercially available form is the monoclinic Datril as it is the most thermodynamically stable polymorph.3
From reappraisal of the literature, it can be concluded that in vivo bioequivalence testing of solid, unwritten IR paracetamol dose signifiers may non be necessary. This can be justified given that a paracetamol preparation can be shown to:
- Quickly fade out under USP guidelines
- Contain merely the acceptable excipients, in usual measures
- Demonstrates disintegration profile similar to cite merchandise under conditions stated in USP guidelines
Statement of Purpose
Aim; hypothesis
The intent of the proposed survey is to compare the disintegration profiles of bioequivalent IR paracetamol readings listed on the PBS. In peculiar, comparing between every readying will be made, instead of an individual comparing against a referent. We hypothesize that there will be no important difference between the disintegration profile of IR paracetamol tablets when dissolved harmonizing to USP specifications.
Methodology
We propose to analyze the disintegration profiles of eight PBS listed bioequivalent paracetamol readings, viz.; APO-paracetamol, Chemmart Paracetamol, Dymadon P, Febridol, Panama ax, Paracetamol Sandoz, Paralgin, and Terry White Chemist’s Paracetamol. Sixteen tablets of each readying will be dissolved in conformity with the USP disintegration trial for tablets and capsules, utilizing 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 proceedings in harmony with pattern by Dominguez et al.34 these aliquots will be examined for paracetamol by UV spectrophotometry at 289nm. This information will be statistically analyzed by ANOVA.
