International Journal of Pharmaceutics 467 (2014) 84–89
Contents lists available at ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Personalised Medicine
Obtaining fast dissolving disintegrating tablets with different doses of melatonin H. Muñoz, H. Castan, B. Clares, M.A. Ruiz * Pharmacy and Pharmaceutical Technology Deparment, School of Pharmacy, University of Granada, Campus de Cartuja s/n., 18071, Granada, Spain
A R T I C L E I N F O
A B S T R A C T
Article history: Received 20 February 2014 Received in revised form 28 March 2014 Accepted 28 March 2014 Available online 1 April 2014
Fast dissolving disintegrating tablets (FDDTs) containing different dosages of melatonin have been manufactured for administration to a specific target population: pediatric patients, having potential difficulties taking other oral forms. The lower dosages (3 and 5 mg) are intended for epileptic children, migraine prevention, neurodevelopmental disability, sleep disorders and blindness. Dosages of 10 and 60 mg are intended for Duchenne muscular dystrophy. Two FDDT groups have been designed, one which has excipients for direct compression and others having direct compression and effervescent excipients. Tablets have been produced having disintegration times of less than 25 s and with friability and hardness values that require no special storage or packaging conditions. ã 2014 Elsevier B.V. All rights reserved.
Keywords: FDDTs Melatonin Polyvinylpyrrolidone Dysphagia Disintegration times Friability
1. Introduction FDDTs are uncovered tablets intended for fast disintegration in the oral cavity prior to being swallowed. According to the definition by the Royal Spanish Pharmacopoeia (RFE), these tablets should disintegrate, when tested, in less than 3 min. This disintegration testing should be conducted at temperatures ranging between 35 and 39 C, simulating the temperature of the oral cavity. Another requirement which these pharmaceutical forms must comply with is that of appropriate mechanical resistance, both for handling as well as for secondary packaging and storage purposes. The tablets must also have ideal organoleptic characteristics. These tablets may be used by individuals having difficulties swallowing, thereby facilitating administration, having been received very positively by patients (Grace, 2006). In some cases, these tablet forms may improve active substance absorption, offering increased bioavailability as compared to other pharmaceutical traditional forms (tablets and capsules), offering oropharyngeal as well as gastrointestinal absorption (Chatap et al., 2007). The active substance portion that is absorbed in this method is not subject to the first pass effect, and thus, higher plasma concentrations of these substances may be achieved.
* Corresponding author at: Pharmacy and Pharmaceutical Technology Department, School of Pharmacy, University of Granada, 18071, Granada, Spain. Tel.: +34 58 243904; fax +34 58 248958. E-mail address: adolfi[email protected] (M. Ruiz). http://dx.doi.org/10.1016/j.ijpharm.2014.03.054 0378-5173/ ã 2014 Elsevier B.V. All rights reserved.
On a technological level, various processes may be applied in the manufacturingof orodispersible tablets. In selecting excipients, rapid dissolution in water, sweet flavor, low viscosity (to improve palatability) and high compressibility are considered. Sugars are commonly used, due to their pleasant taste and successful masking of other flavors, while also being very soluble in water, dissolving quickly in saliva (Bogner and Wilkosz, 2009). Manufacturing techniques are quite varied. In addition to classical tablet manufacturing methods, the use of freeze–drying techniques have also proven highly effective, resulting in the so-called FLAS tablets (Guiseppina et al., 2006). In this study, the classic direct compression method has been used. Conventional tablets obtained via this technique are characterized by a hardness that permits handling and transport resistance. However, they do not offer fast disintegration in the oral cavity (Mizumoto et al., 2003). Therefore, formulations have been created in order to improve disintegration times without affecting the high active substance concentrations, while also offering appropriate degrees of hardness so as to permit primaryand secondary packaging and traditional storage methods (30.4–44.4 N). The active substance used in the manufacturing of these tablets is melatonin, a hormone derived from 5-hidroxytryptamine which is secreted primarily in the pineal gland and the retina of vertebrates during dark hours. Its importance lies in its ability to regulate normal physiological processes related to biorhythms and neuroendocrine function (Flórez and Armijo, 2008). Melatonin production begins with the uptake of the amino acid tryptophan, the majority of which is converted into serotonin.
H. Muñoz et al. / International Journal of Pharmaceutics 467 (2014) 84–89
Acetylation and subsequent O-methylation processes result in melatonin (Axelrod, 1974). Approximately 90% of the melatonin is metabolized and degraded in an initial step taking place in the liver, via 6hydroxylation of the indole ring and in a second step occurring in the kidneys (Kveder and McIsaac, 1961). All of the hormone’s metabolites are excreted in urine, and this excretion is parallel to the circadian rhythms of the hormone. Only 1% is eliminated in urine without suffering any transformation. Of the numerous potential functions of melatonin, those described in this study in regards to the different pharmaceutical forms are of special interest (Cousin et al., 1995; Khanjari et al., 2000). The 3 and 5 mg dosages are intended for use in children treated with valproic acid, as these dosages are found to improve attention, memory and language (Madhur et al., 2004) while decreasing seizure frequency and intensity of crises (Fauteck et al., 1999). Melatonin is also used as a prophylactic for migraine prevention (Miano et al., 2008; Viswanathan, 2001), sleep disorders, children with neurodevelopmental disabilities, jet lag (Wassmer and Whitehouse, 2006) and in blind children (Cavallo et al., 2002). In the case of the 10 and 60 mg dosages, the melatonin acts to alleviate the damaging effect (in children suffering from Duchenne muscular dystrophy) of the hyperoxidative erythrocyte state (Chahbouni et al., 2011; Ruiz and Muñoz, 2013).
(Denmark). The validity of this method is assessed by determining its precision, safety and accuracy. For the manufacturing of the orodispersible melatonin tablets: the Specac pellet press is used (Atlas SeriesTM (Germany)), the manual 15 t press and 5 and 10 mm diameter pellet dies. The galenic trials conducted on the orodispersible tablets, in accordance with those in the Royal Spanish Pharmacopoeia, include (RFE, 2012): I Uniformity of mass using a precision balance such as the A&D
II
III
2. Materials and methods 2.1. Materials IV
To the formulation of fast dissolving disintegrating tablets were employed: Melatonin was purchased from Methapharmaceutical IND S.L. (Spain). Mannitol, polyvinylpyrrolidone (crospovidone), lactose, magnesium stearate, anhydrous coloidal silica, tartaric acid, sodium bicarbonate. All supplied by Fagron Ibérica S.A.U. (Spain). Distilled water. 2.2. Methods In order to ensure that the melatonin responds to official medication provision requirements, a physical–chemical characterization has been carried out via: Desiccation of the active substance in an oven J.P. SELECTA, S.A. (Spain). Determination of pH with a CRISON GLP-type pH-meter (Germany). Verification of the endothermic or exothermic areas of the melatonin via differential scanning calorimetry (DSC) using a Mettler Toledo DSC1 apparatus (USA). The melatonin evaluation is conducted via UV–vis spectrophotometry with the 8500 UV/VIS spectrophotometer, Dyn Co.
85
V
Instruments LTD, GR-202. Some 20 tablets are randomly selected, determining their average mass. The RFE describes the general acceptance criteria, indicating the maximum acceptable deviation based on tablet weight. Friability: With a Roche friability tester such as the ERWEKA GmbH (Germany). Randomly selecting 20 tablets and determining their average mass. The RFE describes the general acceptance criteria, indicating the maximum acceptable deviation based on tablet weight. This test is intended to determine tablet mass lost due to abrasion, under defined conditions. This loss, expressed in percentage, is the friability. For hardness testing, a hardness tester such as the ERWEKA TBH 20 (Germany) is used. It is used to assess resistance to breakage, and is a test which provides indications, not only of tablet’s mechanical stability, but also of decomposition and subsequent dissolution as well as the release of principle actives. When conducting the test, a diametrical, progressive and increasing force is exerted on the tablet until it breaks. The test is conducted on 10 tablets. Disintegration: This test is used to determine the ability of the tablets to disintegrate in a liquid medium over a determined period of time. In order for the orodispersible tablets to comply with the disintegration times indicated in the RFE, disintegration should occur in less than 3 min. For this test, the ERWEKA GmbH (Germany) device is used. Dissolution testing: This test is of considerable importance in tablet quality control, as dissolution of the principle active tends to be the limiting factor for its absorption. This test is described in most pharmacopoeias, utilizing different devices. In this study, the Sotax AT7 Smart (Germany) device was used.
3. Results and discussion 3.1. Analysis of the formulations Our objective is to manufacture small-sized tablets; therefore, two pellet die sizes (5 and 10 mm diameter) were to be used. First, production was undertaken with the smaller-sized dies. A high adherence to the compression chamber was observed, even upon modification of pressures, compression times and lubricating excipients. Thus, it was decided to use the 10 mm diameter pellet die, manufacturing the formulations described in Tables 1 and 2.
Table 1 Fast dissolving disintegrating tablets obtained by direct compression, with classics disintegrations. Formulation
Melatonin (%)
Mannitol (%)
Polyvinylpyrrolidone (%)
Magnesium stearate (%)
Silicio coloidal anhydre (%)
1
2
66.67
28
2
1.33
2
3.33
66.67
26.67
2
1.33
3
6.67
63.33
26.67
2
1.33
4
40
44.67
13.33
1.33
0.66
86
H. Muñoz et al. / International Journal of Pharmaceutics 467 (2014) 84–89
Table 2 Fast dissolving disintegrating tablets obtained by direct compression, with effervescents disintegrations. Formulation
Melatonin (%)
Tartaric acid (%)
Sodium bicarbonate (%)
Polyvinylpyrrolidone (%)
Silice coloidal anhidra (%)
5 6 7 8
2 3.33 6.67 35.29
23.33 23.33 22 17.65
31.33 31.33 30 32.67
42 40.67 40 20
1.33 1.33 1.33 0.67
Table 3 Results of friability, hardness and disintegration time depending on the modifications of press and compression time in formulations 1–3. Formulation
Press (t)
Compression time (s)
Friability (%)
Hardness (N)
Disintegration time (s)
1
1 1.5 1 1.5 1 1.5
10 20 10 30 10 30
1.59 0.97 1.88 0.86 1.61 0.94
22 30.4 23 33.2 24.2 32.5
21 21 22 21 20 25
2 3
polyvinylpyrrolidone (42.6%). Upon application of 1 t of pressure and 30 s of compression in the chamber, the desired results were obtained. All of these results are shown in Table 4. The design of formulations 6 and 7 are based on changes made to formulation 5. In these two cases, in addition to modifying the formulation by substituting the lactose excipient for polyvinylpyrrolidone, both pressure and compression time was increased (from 1 t to 1.5 t of pressure and from 10 s to 30 s for compression time). In formulation 8, lactose was initially eliminated, and this quantity was distributed between the acid and the base (20% tartaric acid and 39.3% sodium bicarbonate), as it was believed that increasing the acid/base ratio would lead to more rapid disintegration and would increase the hardness of the pharmaceutical product. Tablets were created with a pressure of 1 t and with 15 s of compression; the resulting forms were easily broken. Therefore, a progressive increase in pressure was applied (up to 2 t) but problems of low resistance to breakage persisted. Therefore, the formulation was changed, decreasing the acid and base components and adding 11.75% of lactose. Resistance to breakage was then found to be adequate, but disintegration did not comply with RFE standards, as the tablets required over 4 min to disintegrate. The final changes made to the formulation included the elimination of lactose as an excipient, a decrease in the acid/base ratio and the addition of 17.65% of polyvinylpyrrolidone. Upon making these changes, a disintegration value of 26 s was attained and a friability of 0.83%. The modifications made to the formulation are summarized in Table 5.
The 3, 5 and 10 mg tablets corresponding to formulations 1–3 of Table 1 contain a high percentage of mannitol and polyvinylpyrrolidone (PVP). It was found that although they comply with RFE requirements, they are highly friable; therefore, the formulations were modified, increasing pressure and compression time during production. Table 3 shows the obtained results, demonstrating how friability is less than 1% upon modification of these mechanical characteristics. In the case of formulation 4, in order to obtain satisfactory friability results, disaggregation agents (mannitol and polyvinylpyrrolidone) were added in equal parts as well as 0.6% of the anhydrous colloidal silica lubricant. For formulations 5–8 (Table 2), which included the effervescent disaggregates (tartaric acid and sodium bicarbonate), it may be observed that, during the manufacturing of formulation 5, which initially had high quantities of lactose (almost 50% of the total weight) upon 1 t of pressure and 15 s of compression time, the produced tablets were found to be highly friable, breaking easily, although their disintegration time was low (18 s). Upon duplication of the mechanical values, the loss of mass remained quite high in the friability test. Therefore, the formulation was changed, decreasing lactose by 20%, slightly increasing the quantity of tartaric acid and including 13.3% of polyvinylpyrrolidone. Upon making these changes, the friability value was decreased, but it still did not approach the 1% required by the RFE. The next change made was to invert the quantities of lactose and polyvinylpyrrolidone, resulting in a considerable improvement in friability. The final modification was then made, substituting lactose for Table 4 Effect caused by addition of the excipient polyvinylpyrrolidone in formulation 5. Formulation
Modifications
Press (t)
Compression time (s)
Friability (%)
Disintegration time (s)
5
49.3% L/0% P 13.3% P/29.3% L 42.6% P/0% L
1 1.5 1.5
15 30 30
5.49 1.32 0.88
18 25
Table 5 Modifications realized to formulation 8. Influence of polyvinylpyrrolidone addition and the mechanical changes in both friability and disintegration time of these pharmaceuticals forms. Formulation
Modifications
Press (t)
Compression time (s)
Friability (%)
Disintegration time (s)
8
20% A/39.3% B/0% P/0 L 11.75% L 17.65% P/0 L
1 1.5 1.5
15 15 30
>7 300 >240 26
P, polyvinylpyrrolidone; L, lactose; A, tartaric acid; B, sodium bicarbonate.
H. Muñoz et al. / International Journal of Pharmaceutics 467 (2014) 84–89
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Fig. 1. Friability assay of the 8 formulations.
3.2. Galenic assays After designing the definitive formulations, both groups of orodispersible melatonin tablets were subjected to the corresponding galenic assays. 3.2.1. Organoleptic characteristics Color, smell, taste and shape of the pharmaceutical forms created. These may be deciding factors in administration and may potentially exercise a great psychological effect on the patient, increasing or decreasing the success of its use. The designed formulations presented acceptable organoleptic properties. 3.2.2. Dimensions Various tablets are randomly placed on a flat surface for measurement. All of the tablets have height values of 1.58 0.04 mm and diameters of 10.10 0.01 mm. 3.2.3. Mass uniformity This test verifies the homogeneity of the preparation. In conducting the test, 20 randomly selected tablets are weighed individually, and the average mass and standard deviation are determined. No more than 2 of the 20 individual masses deviated
from the average mass in a percentage exceeding 7.5%, and none of them deviated by over double this percentage. The obtained results comply with these requirements. 3.2.4. Friability assay Loss in mass when subjecting 20 tablets (having a weight of less than 650 mg) to 100 rotations in the friability tester should not exceed 1%. For this, the tablets to be analyzed are weighed before and after the test (upon elimination of any dust). Results are expressed as the percentage of mass lost with respect to the initial mass. All results obtained for the FDDTs had values of less than 1%. Fig. 1 shows the friability values for the various orodispersible melatonin tablets. It may be seen that the direct compression tablets (formulations 1–4) had greater losses of mass han those containing effervescent excipients in their composition (formulations 5–8), with the exception of formulation 2, which had the lowest value of loss of its group. In comparison to the effervescent excipients formulations, this formulation had better results than formulation 5. Formulation 7 had the lowest overall loss of mass. This may have been due to the fact that, in addition to the increased pressures and compression times used in formulations 5–8, they also contained higher percentages of polyvinylpyrrolidone, which acts as a super-disintegrant and favors tablet
Fig. 2. Hardness (N) of the 8 formulations.
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H. Muñoz et al. / International Journal of Pharmaceutics 467 (2014) 84–89
Fig. 3. Disintegration time (s) of the 8 formulations.
compression, as seen in the review work of Pathan et al. (2012). Similar results were obtained by Alburyhi and Aboghanem (2013) with artemether/lumefantrine tablets. Differences in friability percentages were influenced by the pressures and compression times used, with formulations 5–8 being the most greatly influenced by these factors. 3.2.5. Hardness test For the hardness test, the RFE method described by the breakage by crushing was implemented. The tablet was placed between the device jaws (10 randomly selected tablets were used), and the hardness tester was activated so that the movable jaw pressed the tablet until breaking it, expressing this force in newton. In Fig. 2 it is seen that, for the first four formulations, formulation 1 had the lowest hardness value, and formulation 3 had the maximum value. For formulations 5–8, the maximum hardness was found in formulation 6, followed by 5, with formulation 8 coming in last. We verified that the greatest hardness values were found in those tablets containing effervescent excipients (influenced, as in the friability test, by the pressure and compression times used),
exceeding those that did not contain effervescent excipients (Samata et al., 2012; Desale et al., 2011). The largest difference in hardness was found between formulations 1 and 5, with an increase of 12.9 points for the latter. Average hardness values were 36.59 1.83 N. 3.2.6. Disintegration times For compliance with the disintegration times indicated in the RFE, the orodispersible tablets should disintegrate in less than 3 min. For this test, the sample was introduced in each of the six device tubes, and the set was placed in a beaker of distilled water at a temperature of 37 C and a pH of 5.99 (simulating saliva conditions). The apparatus was activated, and the time required for complete disintegration was observed. All of the formulations disintegrated in less than 30 s, as shown in Fig. 3. Low disintegration times were achieved through the modifications of excipients (addition or increase of polyvinylpyrrolidone), times and compression pressures. Desale et al. (2011) found improved results in their study upon modification of the mechanical process characteristics and Pathan et al. (2012) and Mehtaa et al. (2012) examined polyvinylpyrrolidone as excellent super-disintegrants.
Fig. 4. Dissolution test of the 8 formulations.
H. Muñoz et al. / International Journal of Pharmaceutics 467 (2014) 84–89
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Without a doubt, both of these factors were responsible for the good results obtained in our study.
the most positive results were those of formulation 6, having a disintegration time of 18 s.
3.2.7. Dissolution test The testing conditions were as follows: temperature of 37 C, time of 30 min, blade rotation speed of 50 rpm all in sufficient volume (distilled water) in order to comply with the “sink” conditions. The number of tablets used for the test is six, plus a blank. Evaluation of the quantity of melatonin freed in the test for the different dosages is conducted by UV–vis spectrophotometry, with a spectral sweep from 400 to 200 nm with 1 nm intervals, in order to determine the longitude of the maximum melatonin absorption wavelength (l = 222 nm). The amount of melatonin free after 30 min for each of the tablets was evaluated by taking 5 ml aliquots and calculating the absorbance (via filtration) in the 8500 UV–vis spectrophotometer for later extrapolation of these values in the previously obtained calibration line, thereby obtaining the concentration of melatonin in each sample. Some 75% of the active substance quantity indicated in each formulation (Q) should be freed after the 30 min period. After this time, the six tablets should have freed a quantity that is not less than Q + 5%. As seen in Fig. 4, with the exception of formulation 1 which had a greater deviation than formulation 6, the non-effervescent excipient formulations had lower deviations (formulations 2 and 3) than the effervescent forms. Of all the collected data, the greatest deviation was found for formulation 1, followed by formulation 4. The obtained results may be due to the mixture of the components, although they comply with the uniformity of mass test, the calculation of the deviation and the standard error of the mean in this test shows higher values for the subsequent formulas, in the dissolution test there are increased deviations.
References
4. Conclusions Orodispersible tablets have been produced via direct compression, having low costs and optimal galenic assays results. Tablets were made with a high dosage of melatonin (60 mg), having a small size and a low disintegration time. Polyvinylpyrrolidone is an excellent binder for this type of tablets, resulting in an orodispersible effervescent tablet that is less friable and has a lower disintegration time. Similarly, orodispersible tablets without effervescence have a lower disintegration time thanks to the increased quantity of polyvinylpyrrolidone in their formulation. Polyvinylpyrrolidone may be considered to act as both a disintegrating and a binding agent. The use of lactose as a diluent in these tablets does not offer sufficient resistance and therefore, is not considered appropriate in these cases. The relationship between the mechanical characteristics employed during production of the different formulations significantly influences the results of the galenic assays. These are parameters to be taken into serious consideration. In our case,
Alburyhi, M., Aboghanem, M.A.A.A., 2013. Effect of different excipients on formulation of immediate release artemether/lumefantrine tablets. Journal of Chemical and Pharmaceutical Research 5, 617–625. Axelrod, 1974. The pineal gland: a neurochemical tranducer. Science 184, 1341– 1348. Bogner, R.H., Wilkosz, M.F., 2009. Fast-dissolving tablets. U.S. Pharmacist. Fast dissolving disintegrating tablets with isomalt. Pharmaceutical Technology Europe 25–28. Cavallo, A., William, V., Douglas, M., Succop, P., 2002. Dose response to melatonin treatment for disordered sleep rhythm in a blind child. Sleep Medicine 3, 159– 161. Chahbouni, M., Escames, G., López, L.C., Sevilla, B., Doerrier, C., Muñoz-Hoyos, A., Molina-Carballo, A., Acuña-Castroviejo, D., 2011. Melatonin treatment counter acts the hyperoxidative status in erythrocytes of patients suffering from Duchenne muscular dystrophy. Clinical Biochemistry Elsevier Inc. 44, 853–858. doi:10.1016/j.clinbiochem.2011.04.001. Chatap, V.K., Gupta, R.D., Jaiswal, N.R., Patidar, V.S., Gupta, V.B., 2007. Recent advances in mouth disintegration tablet technology. Asian Journal of Pharmaceutics 1, 191–195. Cousin, G., Bruna, E., Gendrot, E., 1995. Rapidly disintegradeable multiparticular tablet. US Patent 5, 464, 632. Desale, K.Y., Bankar, V.H., Gaikwad, P.D., Pawar, S.P., 2011. Review on: fast dissolving/ disintegrating tablets. International Journal of Pharmaceutical Sciences Review and Research 11, 152–158. Fauteck, J., Schmidt, H., Lerchl, A., 1999. Melatonin in epilepsy: first results of replacement therapy and first clinical results. Biological Signals and Receptors 8, 105–110. Flórez, J., Armijo, J.A., 2008. Neurotransmisión en el sistema nervioso central. In: Flórez, J. (Ed.), Farmacología Humana. Masson-Salvat Medicina, Barcelona pp. 430, 475–476. Grace, U.E., 2006. Improving medication adherence with orally disintegrating tablets. Nursing 36, 20–21. Guiseppina, S., Bonferoni, Ferrari, F., Rossi, S., Caramella, C., 2006. Differentiating factors between oral fast-dissolving technologies. American Journal of Drug Delivery 4, 249–262. Khanjari, R.K., Hontz, J., Chastain, S.J., Katzner, L., 2000. Rapidly dissolving robust dosage form. US Patent 6, 024, 981. Kveder, S., McIsaac, W.M., 1961. The metabolism of melatonin (N-acetylmethoxytryptamine) and 5-metoxy-triptamine. Journal of Biological Chemistry 236, 3214–3220. Madhur, G., Satinder, A., Kamlesh, K., 2004. Add-on melatonin improves quality of life in epileptic children on valproate monotherapy: a randomized, doubleblind, placebo-controlled trial. Epilepsy & Behavior 5, 316–321. doi:10.1016/j. yebeh.2004.01.012. Mehtaa, S., Beerb, T., Remona, J.P., Vervaeta, C., 2012. Effect of disintegrants on the properties of multiparticulate tablets comprising starch pellets and excipient granules. International Journal of Pharmaceutics 422, 310–317. Miano, S., Parisi, P., Plliccia, A., Luchetti, A., Paolino, M.C., Villa, M.P., 2008. Melatonin to prevent migraine or tension-type headache in children. Neurological Sciences 29, 285–287. Mizumoto, T., Masuda, Y., Kajiyama, A., Yanagisawa, M., Nyshadham, J.R., 2003. Tablets quickly disintegrating in the oral cavity and process for producing the same. US Patent 6,589,554. Pathan, V.T., Rane, B.R., Gujarathi, N.A., Bakliwai, S.R., Pawar, S.P., 2012. A review on “Novel concept of oral fast dissolving tablet”. Pharmaceutical Research 8, 15–37. Real Farmacopea Española, Ministerio de Sanidad y Consumo Website. 4 Ed. 2010. http://tienda.boe.es/Farmacopea_index.html (accessed on July 2012). Ruiz, A., Muñoz, H., 2013. Composición bucodispersable de melatonina. ES Patent P201231477. Samata, M., De Beer, T., Remon, J.P., Vervaet, C., 2012. Effect of disintegrants on the properties of multiparticulate tablets comprising starch pellets and excipient granules. International Journal of Pharmaceutics 422, 310–317. Viswanathan, M., 2001. Melatonin inhibits calcitonin gene-related peptide-induced vasodilation and increase in cAMP in rat middle cerebral arteries. European Journal of Pharmacology 415, 247–250. Wassmer, E., Whitehouse, W.P., 2006. Melatonin and sleep in children with neurodevelopmental disabilities and sleep disorders. Current Paediatrics 16, 132–138. doi:10.1016/cupe.2006.01.001.
Contents lists available at ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Personalised Medicine
Obtaining fast dissolving disintegrating tablets with different doses of melatonin H. Muñoz, H. Castan, B. Clares, M.A. Ruiz * Pharmacy and Pharmaceutical Technology Deparment, School of Pharmacy, University of Granada, Campus de Cartuja s/n., 18071, Granada, Spain
A R T I C L E I N F O
A B S T R A C T
Article history: Received 20 February 2014 Received in revised form 28 March 2014 Accepted 28 March 2014 Available online 1 April 2014
Fast dissolving disintegrating tablets (FDDTs) containing different dosages of melatonin have been manufactured for administration to a specific target population: pediatric patients, having potential difficulties taking other oral forms. The lower dosages (3 and 5 mg) are intended for epileptic children, migraine prevention, neurodevelopmental disability, sleep disorders and blindness. Dosages of 10 and 60 mg are intended for Duchenne muscular dystrophy. Two FDDT groups have been designed, one which has excipients for direct compression and others having direct compression and effervescent excipients. Tablets have been produced having disintegration times of less than 25 s and with friability and hardness values that require no special storage or packaging conditions. ã 2014 Elsevier B.V. All rights reserved.
Keywords: FDDTs Melatonin Polyvinylpyrrolidone Dysphagia Disintegration times Friability
1. Introduction FDDTs are uncovered tablets intended for fast disintegration in the oral cavity prior to being swallowed. According to the definition by the Royal Spanish Pharmacopoeia (RFE), these tablets should disintegrate, when tested, in less than 3 min. This disintegration testing should be conducted at temperatures ranging between 35 and 39 C, simulating the temperature of the oral cavity. Another requirement which these pharmaceutical forms must comply with is that of appropriate mechanical resistance, both for handling as well as for secondary packaging and storage purposes. The tablets must also have ideal organoleptic characteristics. These tablets may be used by individuals having difficulties swallowing, thereby facilitating administration, having been received very positively by patients (Grace, 2006). In some cases, these tablet forms may improve active substance absorption, offering increased bioavailability as compared to other pharmaceutical traditional forms (tablets and capsules), offering oropharyngeal as well as gastrointestinal absorption (Chatap et al., 2007). The active substance portion that is absorbed in this method is not subject to the first pass effect, and thus, higher plasma concentrations of these substances may be achieved.
* Corresponding author at: Pharmacy and Pharmaceutical Technology Department, School of Pharmacy, University of Granada, 18071, Granada, Spain. Tel.: +34 58 243904; fax +34 58 248958. E-mail address: adolfi[email protected] (M. Ruiz). http://dx.doi.org/10.1016/j.ijpharm.2014.03.054 0378-5173/ ã 2014 Elsevier B.V. All rights reserved.
On a technological level, various processes may be applied in the manufacturingof orodispersible tablets. In selecting excipients, rapid dissolution in water, sweet flavor, low viscosity (to improve palatability) and high compressibility are considered. Sugars are commonly used, due to their pleasant taste and successful masking of other flavors, while also being very soluble in water, dissolving quickly in saliva (Bogner and Wilkosz, 2009). Manufacturing techniques are quite varied. In addition to classical tablet manufacturing methods, the use of freeze–drying techniques have also proven highly effective, resulting in the so-called FLAS tablets (Guiseppina et al., 2006). In this study, the classic direct compression method has been used. Conventional tablets obtained via this technique are characterized by a hardness that permits handling and transport resistance. However, they do not offer fast disintegration in the oral cavity (Mizumoto et al., 2003). Therefore, formulations have been created in order to improve disintegration times without affecting the high active substance concentrations, while also offering appropriate degrees of hardness so as to permit primaryand secondary packaging and traditional storage methods (30.4–44.4 N). The active substance used in the manufacturing of these tablets is melatonin, a hormone derived from 5-hidroxytryptamine which is secreted primarily in the pineal gland and the retina of vertebrates during dark hours. Its importance lies in its ability to regulate normal physiological processes related to biorhythms and neuroendocrine function (Flórez and Armijo, 2008). Melatonin production begins with the uptake of the amino acid tryptophan, the majority of which is converted into serotonin.
H. Muñoz et al. / International Journal of Pharmaceutics 467 (2014) 84–89
Acetylation and subsequent O-methylation processes result in melatonin (Axelrod, 1974). Approximately 90% of the melatonin is metabolized and degraded in an initial step taking place in the liver, via 6hydroxylation of the indole ring and in a second step occurring in the kidneys (Kveder and McIsaac, 1961). All of the hormone’s metabolites are excreted in urine, and this excretion is parallel to the circadian rhythms of the hormone. Only 1% is eliminated in urine without suffering any transformation. Of the numerous potential functions of melatonin, those described in this study in regards to the different pharmaceutical forms are of special interest (Cousin et al., 1995; Khanjari et al., 2000). The 3 and 5 mg dosages are intended for use in children treated with valproic acid, as these dosages are found to improve attention, memory and language (Madhur et al., 2004) while decreasing seizure frequency and intensity of crises (Fauteck et al., 1999). Melatonin is also used as a prophylactic for migraine prevention (Miano et al., 2008; Viswanathan, 2001), sleep disorders, children with neurodevelopmental disabilities, jet lag (Wassmer and Whitehouse, 2006) and in blind children (Cavallo et al., 2002). In the case of the 10 and 60 mg dosages, the melatonin acts to alleviate the damaging effect (in children suffering from Duchenne muscular dystrophy) of the hyperoxidative erythrocyte state (Chahbouni et al., 2011; Ruiz and Muñoz, 2013).
(Denmark). The validity of this method is assessed by determining its precision, safety and accuracy. For the manufacturing of the orodispersible melatonin tablets: the Specac pellet press is used (Atlas SeriesTM (Germany)), the manual 15 t press and 5 and 10 mm diameter pellet dies. The galenic trials conducted on the orodispersible tablets, in accordance with those in the Royal Spanish Pharmacopoeia, include (RFE, 2012): I Uniformity of mass using a precision balance such as the A&D
II
III
2. Materials and methods 2.1. Materials IV
To the formulation of fast dissolving disintegrating tablets were employed: Melatonin was purchased from Methapharmaceutical IND S.L. (Spain). Mannitol, polyvinylpyrrolidone (crospovidone), lactose, magnesium stearate, anhydrous coloidal silica, tartaric acid, sodium bicarbonate. All supplied by Fagron Ibérica S.A.U. (Spain). Distilled water. 2.2. Methods In order to ensure that the melatonin responds to official medication provision requirements, a physical–chemical characterization has been carried out via: Desiccation of the active substance in an oven J.P. SELECTA, S.A. (Spain). Determination of pH with a CRISON GLP-type pH-meter (Germany). Verification of the endothermic or exothermic areas of the melatonin via differential scanning calorimetry (DSC) using a Mettler Toledo DSC1 apparatus (USA). The melatonin evaluation is conducted via UV–vis spectrophotometry with the 8500 UV/VIS spectrophotometer, Dyn Co.
85
V
Instruments LTD, GR-202. Some 20 tablets are randomly selected, determining their average mass. The RFE describes the general acceptance criteria, indicating the maximum acceptable deviation based on tablet weight. Friability: With a Roche friability tester such as the ERWEKA GmbH (Germany). Randomly selecting 20 tablets and determining their average mass. The RFE describes the general acceptance criteria, indicating the maximum acceptable deviation based on tablet weight. This test is intended to determine tablet mass lost due to abrasion, under defined conditions. This loss, expressed in percentage, is the friability. For hardness testing, a hardness tester such as the ERWEKA TBH 20 (Germany) is used. It is used to assess resistance to breakage, and is a test which provides indications, not only of tablet’s mechanical stability, but also of decomposition and subsequent dissolution as well as the release of principle actives. When conducting the test, a diametrical, progressive and increasing force is exerted on the tablet until it breaks. The test is conducted on 10 tablets. Disintegration: This test is used to determine the ability of the tablets to disintegrate in a liquid medium over a determined period of time. In order for the orodispersible tablets to comply with the disintegration times indicated in the RFE, disintegration should occur in less than 3 min. For this test, the ERWEKA GmbH (Germany) device is used. Dissolution testing: This test is of considerable importance in tablet quality control, as dissolution of the principle active tends to be the limiting factor for its absorption. This test is described in most pharmacopoeias, utilizing different devices. In this study, the Sotax AT7 Smart (Germany) device was used.
3. Results and discussion 3.1. Analysis of the formulations Our objective is to manufacture small-sized tablets; therefore, two pellet die sizes (5 and 10 mm diameter) were to be used. First, production was undertaken with the smaller-sized dies. A high adherence to the compression chamber was observed, even upon modification of pressures, compression times and lubricating excipients. Thus, it was decided to use the 10 mm diameter pellet die, manufacturing the formulations described in Tables 1 and 2.
Table 1 Fast dissolving disintegrating tablets obtained by direct compression, with classics disintegrations. Formulation
Melatonin (%)
Mannitol (%)
Polyvinylpyrrolidone (%)
Magnesium stearate (%)
Silicio coloidal anhydre (%)
1
2
66.67
28
2
1.33
2
3.33
66.67
26.67
2
1.33
3
6.67
63.33
26.67
2
1.33
4
40
44.67
13.33
1.33
0.66
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Table 2 Fast dissolving disintegrating tablets obtained by direct compression, with effervescents disintegrations. Formulation
Melatonin (%)
Tartaric acid (%)
Sodium bicarbonate (%)
Polyvinylpyrrolidone (%)
Silice coloidal anhidra (%)
5 6 7 8
2 3.33 6.67 35.29
23.33 23.33 22 17.65
31.33 31.33 30 32.67
42 40.67 40 20
1.33 1.33 1.33 0.67
Table 3 Results of friability, hardness and disintegration time depending on the modifications of press and compression time in formulations 1–3. Formulation
Press (t)
Compression time (s)
Friability (%)
Hardness (N)
Disintegration time (s)
1
1 1.5 1 1.5 1 1.5
10 20 10 30 10 30
1.59 0.97 1.88 0.86 1.61 0.94
22 30.4 23 33.2 24.2 32.5
21 21 22 21 20 25
2 3
polyvinylpyrrolidone (42.6%). Upon application of 1 t of pressure and 30 s of compression in the chamber, the desired results were obtained. All of these results are shown in Table 4. The design of formulations 6 and 7 are based on changes made to formulation 5. In these two cases, in addition to modifying the formulation by substituting the lactose excipient for polyvinylpyrrolidone, both pressure and compression time was increased (from 1 t to 1.5 t of pressure and from 10 s to 30 s for compression time). In formulation 8, lactose was initially eliminated, and this quantity was distributed between the acid and the base (20% tartaric acid and 39.3% sodium bicarbonate), as it was believed that increasing the acid/base ratio would lead to more rapid disintegration and would increase the hardness of the pharmaceutical product. Tablets were created with a pressure of 1 t and with 15 s of compression; the resulting forms were easily broken. Therefore, a progressive increase in pressure was applied (up to 2 t) but problems of low resistance to breakage persisted. Therefore, the formulation was changed, decreasing the acid and base components and adding 11.75% of lactose. Resistance to breakage was then found to be adequate, but disintegration did not comply with RFE standards, as the tablets required over 4 min to disintegrate. The final changes made to the formulation included the elimination of lactose as an excipient, a decrease in the acid/base ratio and the addition of 17.65% of polyvinylpyrrolidone. Upon making these changes, a disintegration value of 26 s was attained and a friability of 0.83%. The modifications made to the formulation are summarized in Table 5.
The 3, 5 and 10 mg tablets corresponding to formulations 1–3 of Table 1 contain a high percentage of mannitol and polyvinylpyrrolidone (PVP). It was found that although they comply with RFE requirements, they are highly friable; therefore, the formulations were modified, increasing pressure and compression time during production. Table 3 shows the obtained results, demonstrating how friability is less than 1% upon modification of these mechanical characteristics. In the case of formulation 4, in order to obtain satisfactory friability results, disaggregation agents (mannitol and polyvinylpyrrolidone) were added in equal parts as well as 0.6% of the anhydrous colloidal silica lubricant. For formulations 5–8 (Table 2), which included the effervescent disaggregates (tartaric acid and sodium bicarbonate), it may be observed that, during the manufacturing of formulation 5, which initially had high quantities of lactose (almost 50% of the total weight) upon 1 t of pressure and 15 s of compression time, the produced tablets were found to be highly friable, breaking easily, although their disintegration time was low (18 s). Upon duplication of the mechanical values, the loss of mass remained quite high in the friability test. Therefore, the formulation was changed, decreasing lactose by 20%, slightly increasing the quantity of tartaric acid and including 13.3% of polyvinylpyrrolidone. Upon making these changes, the friability value was decreased, but it still did not approach the 1% required by the RFE. The next change made was to invert the quantities of lactose and polyvinylpyrrolidone, resulting in a considerable improvement in friability. The final modification was then made, substituting lactose for Table 4 Effect caused by addition of the excipient polyvinylpyrrolidone in formulation 5. Formulation
Modifications
Press (t)
Compression time (s)
Friability (%)
Disintegration time (s)
5
49.3% L/0% P 13.3% P/29.3% L 42.6% P/0% L
1 1.5 1.5
15 30 30
5.49 1.32 0.88
18 25
Table 5 Modifications realized to formulation 8. Influence of polyvinylpyrrolidone addition and the mechanical changes in both friability and disintegration time of these pharmaceuticals forms. Formulation
Modifications
Press (t)
Compression time (s)
Friability (%)
Disintegration time (s)
8
20% A/39.3% B/0% P/0 L 11.75% L 17.65% P/0 L
1 1.5 1.5
15 15 30
>7 300 >240 26
P, polyvinylpyrrolidone; L, lactose; A, tartaric acid; B, sodium bicarbonate.
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Fig. 1. Friability assay of the 8 formulations.
3.2. Galenic assays After designing the definitive formulations, both groups of orodispersible melatonin tablets were subjected to the corresponding galenic assays. 3.2.1. Organoleptic characteristics Color, smell, taste and shape of the pharmaceutical forms created. These may be deciding factors in administration and may potentially exercise a great psychological effect on the patient, increasing or decreasing the success of its use. The designed formulations presented acceptable organoleptic properties. 3.2.2. Dimensions Various tablets are randomly placed on a flat surface for measurement. All of the tablets have height values of 1.58 0.04 mm and diameters of 10.10 0.01 mm. 3.2.3. Mass uniformity This test verifies the homogeneity of the preparation. In conducting the test, 20 randomly selected tablets are weighed individually, and the average mass and standard deviation are determined. No more than 2 of the 20 individual masses deviated
from the average mass in a percentage exceeding 7.5%, and none of them deviated by over double this percentage. The obtained results comply with these requirements. 3.2.4. Friability assay Loss in mass when subjecting 20 tablets (having a weight of less than 650 mg) to 100 rotations in the friability tester should not exceed 1%. For this, the tablets to be analyzed are weighed before and after the test (upon elimination of any dust). Results are expressed as the percentage of mass lost with respect to the initial mass. All results obtained for the FDDTs had values of less than 1%. Fig. 1 shows the friability values for the various orodispersible melatonin tablets. It may be seen that the direct compression tablets (formulations 1–4) had greater losses of mass han those containing effervescent excipients in their composition (formulations 5–8), with the exception of formulation 2, which had the lowest value of loss of its group. In comparison to the effervescent excipients formulations, this formulation had better results than formulation 5. Formulation 7 had the lowest overall loss of mass. This may have been due to the fact that, in addition to the increased pressures and compression times used in formulations 5–8, they also contained higher percentages of polyvinylpyrrolidone, which acts as a super-disintegrant and favors tablet
Fig. 2. Hardness (N) of the 8 formulations.
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Fig. 3. Disintegration time (s) of the 8 formulations.
compression, as seen in the review work of Pathan et al. (2012). Similar results were obtained by Alburyhi and Aboghanem (2013) with artemether/lumefantrine tablets. Differences in friability percentages were influenced by the pressures and compression times used, with formulations 5–8 being the most greatly influenced by these factors. 3.2.5. Hardness test For the hardness test, the RFE method described by the breakage by crushing was implemented. The tablet was placed between the device jaws (10 randomly selected tablets were used), and the hardness tester was activated so that the movable jaw pressed the tablet until breaking it, expressing this force in newton. In Fig. 2 it is seen that, for the first four formulations, formulation 1 had the lowest hardness value, and formulation 3 had the maximum value. For formulations 5–8, the maximum hardness was found in formulation 6, followed by 5, with formulation 8 coming in last. We verified that the greatest hardness values were found in those tablets containing effervescent excipients (influenced, as in the friability test, by the pressure and compression times used),
exceeding those that did not contain effervescent excipients (Samata et al., 2012; Desale et al., 2011). The largest difference in hardness was found between formulations 1 and 5, with an increase of 12.9 points for the latter. Average hardness values were 36.59 1.83 N. 3.2.6. Disintegration times For compliance with the disintegration times indicated in the RFE, the orodispersible tablets should disintegrate in less than 3 min. For this test, the sample was introduced in each of the six device tubes, and the set was placed in a beaker of distilled water at a temperature of 37 C and a pH of 5.99 (simulating saliva conditions). The apparatus was activated, and the time required for complete disintegration was observed. All of the formulations disintegrated in less than 30 s, as shown in Fig. 3. Low disintegration times were achieved through the modifications of excipients (addition or increase of polyvinylpyrrolidone), times and compression pressures. Desale et al. (2011) found improved results in their study upon modification of the mechanical process characteristics and Pathan et al. (2012) and Mehtaa et al. (2012) examined polyvinylpyrrolidone as excellent super-disintegrants.
Fig. 4. Dissolution test of the 8 formulations.
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Without a doubt, both of these factors were responsible for the good results obtained in our study.
the most positive results were those of formulation 6, having a disintegration time of 18 s.
3.2.7. Dissolution test The testing conditions were as follows: temperature of 37 C, time of 30 min, blade rotation speed of 50 rpm all in sufficient volume (distilled water) in order to comply with the “sink” conditions. The number of tablets used for the test is six, plus a blank. Evaluation of the quantity of melatonin freed in the test for the different dosages is conducted by UV–vis spectrophotometry, with a spectral sweep from 400 to 200 nm with 1 nm intervals, in order to determine the longitude of the maximum melatonin absorption wavelength (l = 222 nm). The amount of melatonin free after 30 min for each of the tablets was evaluated by taking 5 ml aliquots and calculating the absorbance (via filtration) in the 8500 UV–vis spectrophotometer for later extrapolation of these values in the previously obtained calibration line, thereby obtaining the concentration of melatonin in each sample. Some 75% of the active substance quantity indicated in each formulation (Q) should be freed after the 30 min period. After this time, the six tablets should have freed a quantity that is not less than Q + 5%. As seen in Fig. 4, with the exception of formulation 1 which had a greater deviation than formulation 6, the non-effervescent excipient formulations had lower deviations (formulations 2 and 3) than the effervescent forms. Of all the collected data, the greatest deviation was found for formulation 1, followed by formulation 4. The obtained results may be due to the mixture of the components, although they comply with the uniformity of mass test, the calculation of the deviation and the standard error of the mean in this test shows higher values for the subsequent formulas, in the dissolution test there are increased deviations.
References
4. Conclusions Orodispersible tablets have been produced via direct compression, having low costs and optimal galenic assays results. Tablets were made with a high dosage of melatonin (60 mg), having a small size and a low disintegration time. Polyvinylpyrrolidone is an excellent binder for this type of tablets, resulting in an orodispersible effervescent tablet that is less friable and has a lower disintegration time. Similarly, orodispersible tablets without effervescence have a lower disintegration time thanks to the increased quantity of polyvinylpyrrolidone in their formulation. Polyvinylpyrrolidone may be considered to act as both a disintegrating and a binding agent. The use of lactose as a diluent in these tablets does not offer sufficient resistance and therefore, is not considered appropriate in these cases. The relationship between the mechanical characteristics employed during production of the different formulations significantly influences the results of the galenic assays. These are parameters to be taken into serious consideration. In our case,
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