AU2009224801A1

AU2009224801A1 - Modified release composition comprising doxofylline

Info

Publication number: AU2009224801A1
Application number: AU2009224801A
Authority: AU
Inventors: Suresh Bandari; Ramesh Gannu; Bodapunti Prabha Shankar; Madhusudan Rao Yamsani; Frederick Van Gulik
Original assignee: Eurodrug Laboratories BV
Current assignee: Pacific Healthcare Thailand Co Ltd
Priority date: 2008-03-10
Filing date: 2009-03-06
Publication date: 2009-09-17
Anticipated expiration: 2029-03-06
Also published as: BRPI0906158B1; MX2010009917A; MX2008010233A; BRPI0906158A2; WO2009112436A1; ITMI20080798A1; KR20100124860A; BRPI0906158B8; EP2262485A1; WO2009112874A1; AU2009224801B2; KR101697773B1

Description

WO 2009/112436 PCT/EP2009/052675 "MODIFIED RELEASE COMPOSITION COMPRISING DOXOFYLLINE" **** ** *** FIELD OF THE INVENTION The present invention concerns a new pharmaceutical composition comprising 5 doxofylline, in particular a modified release formulation, for administration once a day only. TECHNICAL BACKGROUND Doxofylline (7-(1,3-dioxalan-2-ylmethyl)-theophylline) is a drug derived from theophylline which is used in therapy as a bronchodilator, with anti-inflammatory 10 action, in reversible airway obstruction. It is commonly administered in doses ranging from 800 to 1200 mg per day, orally, according to a dosage which provides for the intake of two to three dosage units per day in order to maintain therapeutically effective haematic levels. The doxofylline tablets commercially available generally contain 400 mg of active 15 ingredient and release almost all the drug within one hour from intake. The half life of the drug is around 6-7 hours and for this reason several administrations are required during the 24-hour period. Obviously a drop in haematic concentration of the drug in an asthmatic patient or patient suffering from COPD (chronic obstructive pulmonary disease) can result in serious consequences, in which case 20 the patient must have recourse to rescue medication, such as salbutamol inhalers. Pharmaceutical techniques for obtaining the modified release of drugs have been known for some time, but no modified release formulation of doxofylline is known. In fact the present inventors have observed that there are significant 25 difficulties in the production of a doxofylline formula that can be administered only once a day and in particular have encountered problems correlated with bioequivalence. Various attempts to formulate doxofylline in modified release systems, with different known polymers, have not provided the desired results, i.e. a composition that can be administered once a day, bioequivalent to the plasmatic 30 concentration obtained with the traditional compositions currently on sale. In fact currently, dosage units containing 400 mg of active ingredient are currently

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WO 2009/112436 PCT/EP2009/052675 administered two/three times a day for a daily average of approximately 1000 mg of active ingredient, a dosage considered necessary to maintain the therapeutic haematic levels of doxofylline. Such a dosage unit is currently marketed by Dr. Reddy's Laboratories Ltd as DOXOBID and has the following quali-quantitative 5 composition: doxofylline (400 mg), colloidal silicon dioxide (13 mg), corn starch (63 mg), mannitol (40 mg), povidone (7 mg), microcrystalline cellulose (64 mg), talc (30 mg), magnesium stearate (3 mg) and water (0.08 ml). OBJECTS OF THE INVENTION One object of the present invention is to provide a modified release composition 10 of doxofylline which is bioequivalent to the therapy currently used and which eliminates the need to take several doses per day, thus improving patient compliance. A further object of the present invention is to provide a composition of doxofylline which lowers the initial haematic peak and the first-pass effect 15 occurring in the conventional compositions. A further object of the present invention is to provide a doxofylline composition which maintains the effective concentration of the drug in the blood sufficient to exert the bronchodilatory and anti-inflammatory effect over the 24-hour period, thus reducing the risk of bronchospasm and serious consequences for the patient. 20 Another object of the present invention is to provide a modified release doxofylline composition which avoids the need for recourse to rescue medication, such as salbutamol inhalers, to overcome acute asthmatic attacks and bronchospasms. The above objects have been unexpectedly achieved with the composition of the 25 invention which moreover comprises a surprisingly lower dose of active ingredient than the daily dose commonly used. DESCRIPTION OF THE INVENTION According to one of its embodiments, the invention concerns a modified release pharmaceutical composition which comprises as active ingredient doxofylline, 30 and a polymer selected from a pharmaceutically acceptable cellulose derivative, a pharmaceutically acceptable methacrylate derivative, their mixtures, and 2 WO 2009/112436 PCT/EP2009/052675 pharmaceutically acceptable salts thereof. Doxofylline (or doxophylline) (7-(1,3-dioxalan-2-ylmethyl)-theophylline) has the following structural formula 0 N N / N N

CH

3 5 and is here also called "active ingredient" or "API" (Active Pharmaceutical Ingredient). According to the present invention, "modified release pharmaceutical composition" indicates a pharmaceutical composition that retains the active ingredient for a longer period of time than the conventional compositions and 10 releases it slowly in order to maintain at length the plasmatic concentrations of the drug sufficient to exert the desired therapeutic effect. Said formulation is here also called "BET" (Bioavailability Enhancing Technology) or "TOP" (Technology Optimized Performance) formulation. The term "polymer" indicates, according to the present invention, a 15 pharmaceutically acceptable release modulator polymer or copolymer, suitable for prolonging the release time of the active ingredient from the composition. Said polymer will be indicated below also simply as "release modulator polymer". The expression "pharmaceutically acceptable cellulose derivative" indicates a derivative suitable for prolonging the release time of the drug from the 20 composition, such as pharmaceutically acceptable cellulose esters and ethers, like methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, their mixtures and their salts. 25 The expression "pharmaceutically acceptable methacrylate derivative" indicates a derivative suitable for prolonging the release time of the drug from the 3 WO 2009/112436 PCT/EP2009/052675 composition, for example the copolymer methacrylic acid/methyl methacrylate, the copolymer methacrylic acid/ethyl methacrylate, their mixtures and their salts. According to EMEA (2001) and US FDA (2003) guidelines, herein incorporated by reference, "bioequivalence" is demonstrated if the 90% confidence interval of 5 the AUC falls within an acceptance interval of 80% to 125%. A preferred release modulator polymer according to the invention is a pharmaceutically acceptable cellulose derivative, advantageously selected from methyl cellulose, ethyl cellulose, hydroxyalkyl cellulose (such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose) and their mixtures. 10 The composition of the invention is preferably a composition in the form of a dosage unit suitable for oral administration once a day, advantageously in the form of a tablet. The composition of the invention preferably also comprises excipients useful for the processing thereof, for example lubricating agents, such as magnesium 15 stearate, filling agents, such as lactose, talc, microcrystalline cellulose, agents aiding compression and, if necessary or desired, other excipients such as aromatizers, sweeteners, preservatives, etc., well known to a person skilled in the art. According to a preferred embodiment of the invention comprises a quantity of 20 active ingredient between 550 and 800 mg, preferably between 600 and 750, more preferably between 625 and 700 mg, advantageously around 650 mg. It is understood that said dose can vary according to the age, weight and state of health of the patient. It has been unexpectedly observed, however, during the bioequivalence assays, that it is not necessary to administer a quantity of active 25 ingredient equal to the daily dosage of the conventional compositions currently on the market (commonly administered at a dose of 400 mg twice daily), but that thanks to the composition of the invention, it is possible to obtain a bioequivalent plasmatic concentration even at a very low dosage, for example with 650 mg of active ingredient. 30 This unexpected fact is particularly important as it allows to obtain the same therapeutic effect with a lower dose, even approximately 35% lower, of active 4 WO 2009/112436 PCT/EP2009/052675 ingredient and therefore results in a reduction in side effects and therefore an important benefit for the patient, and at the same time a reduction in industrial costs due to the production and processing of the active ingredient. According to a particularly preferred aspect, the invention concerns a modified 5 release composition which comprises as active ingredient approximately 650 mg of doxofylline and a release modulator polymer as defined above, advantageously in combination with a filling agent and/or a lubricant. The release modulator polymers are used alone or mixed together, in quantities between 30 mg and 200 mg per tablet, preferably between 40 mg and 130 mg, 10 more preferably between 120 and 130 mg; for example, 50, 100 or 125 mg, per dosage unit. The composition of the invention has proved to be particularly suitable for modified release of the active ingredient and with one single oral administration allows an effective haematic concentration of doxofylline to be maintained for 24 15 hours, while at the same time avoiding the excessive haematic peaks after the first and particularly after the second daily administration, which characterise the conventional compositions currently on sale. The preferred composition of the invention advantageously also comprises a lubricant, for example magnesium stearate, for example in quantities between 1 20 and 15 mg, preferably between 3 and 10 mg, for example approximately 5 mg, per dosage unit. The preferred composition of the invention advantageously also comprises one or more filling agents, such as talc, lactose or microcrystalline cellulose, for example in total quantities of between 10 and 200 mg, preferably between 20 and 150 mg, 25 advantageously 30, 50, 70 or 100 mg, per dosage unit; according to a first particularly preferred embodiment, the composition contains between 100 and 150 mg of filling agent; according to a second particularly preferred embodiment, the composition contains both talc and microcrystalline cellulose. According to the best embodiment of the invention, the composition comprises 30 between 625 and 675 mg of doxofylline, between 100 and 150 mg of hydroxypropylmethyl cellulose, between 75 and 125 mg of microcrystalline 5 WO 2009/112436 PCT/EP2009/052675 cellulose, between 15 and 20 mg of talc and between 5 and 10 mg of magnesium stearate; more preferably, the composition comprises 650 mg of doxofylline, 125 mg of hydroxypropylmethyl cellulose, 100 mg of microcrystalline cellulose, 18 mg of talc and 7 mg of magnesium stearate. 5 The composition of the invention is preferably in the form of a tablet and can be prepared by mixing the active ingredient, the release modulator polymer (or the mixture of polymers) and any other components and compressing them to an appropriate hardness, according to the methods known in the art. According to another of its aspects, the invention concerns use of the composition 10 of the invention for the preparation of a bronchodilatory medication with anti inflammatory action for the treatment of all forms of asthma and chronic obstructive pulmonary disease (COPD). According to a further aspect, the invention concerns use of the composition of the invention for the preparation of a medication for oral administration once a 15 day only. According to another of its aspects, the invention concerns a method for the bronchodilatory treatment of all forms of asthma and chronic obstructive pulmonary disease (COPD) which comprises administration to a patient in need thereof of a therapeutically effective amount of the composition of the invention. 20 According to another of its aspects, the invention concerns a method for improving bioavailability of doxofylline in a human being, which method comprises administering to said human being the composition of the invention; more in details, it concerns a method for obtaining in a human being a plasmatic level bioequivalent to that obtainable by administering twice a day an immediate 25 release composition containing 400 mg of doxofylline (such as DOXOBID), which method comprises administering the composition of the invention once a day. According to another of its aspects, the invention comprises a process for preparation of the composition of the invention, in the form of tablets, which 30 comprises: (a) mixing the doxofylline with the release modulator polymer 6 WO 2009/112436 PCT/EP2009/052675 and optionally a filling agent; (b) pre-compressing the mixture (a); (c) grinding the mixture compressed in (b); (d) optionally mixing the mixture ground in (c) with the other 5 desired excipients; (e) compressing the mixture (d). According to another preferred aspect, in phase (b) compressing is performed to obtain a tablet hardness of between 1 and 3 kg/cm 2 . According to a further preferred aspect, in phase (d) a lubricating agent and/or a 10 filling agent are mixed. The examples given in the experimental section of the present description provide embodiments illustrating the composition of the present invention. The composition of the invention can also be formulated in the form of coated pellets. 15 The compositions of the invention have undergone various tests to assess their dissolution profile and stability, as well as their in vivo bioavailability. The tests conducted enabled us to conclude that the composition of the invention, in particular the preferred composition in the form of a tablet, as defined above, is stable and has an optimal dissolution profile for maintaining the haematic 20 concentration of doxofylline effective for 24 hours. Furthermore, the bioavailability tests conducted on the preferred composition in the form of a tablet, as defined above, provided excellent results and, when compared with the conventional compositions (for example 400 mg two/three times a day) of doxofylline, they showed an unexpected improvement in 25 bioavailability. The compositions of the invention are therefore suitable for administration once a day only and, surprisingly, at a dosage even approximately 35% lower than the average daily dosage of the conventional formulations. EXPERIMENTAL SECTION EXAMPLE 1 30 A modified release composition in tablet form is prepared which contains, for each tablet: 7 WO 2009/112436 PCT/EP2009/052675 e doxofylline 650.00 mg e hydroxypropylmethyl cellulose 50.00 mg e microcrystalline cellulose 30.00 mg e magnesium stearate 5.00 mg 5 EXAMPLE 2 A modified release composition in tablet form is prepared which contains, for each tablet: e doxofylline 650.00 mg e hydroxypropylmethyl cellulose 125.00 mg 10 e microcrystalline cellulose 100.00 mg e magnesium stearate 7.00 mg talc 18.00 mg EXAMPLE 3 A modified release composition in tablet form is prepared which contains, for 15 each tablet: e doxofylline 600.00 mg e hydroxypropylmethyl cellulose 50.00 mg e microcrystalline cellulose 30.00 mg e magnesium stearate 5.00 mg 20 EXAMPLE 4 A randomized, open-label, balanced, three-treatment, three-period, three sequence, single dose, crossover bioavailability study has been done in twelve healthy, adult, male, human subjects under fasting conditions using the 650 mg tablet of example 2 (Doxofylline SR 650) the 600 mg tablet of example 3 25 (Doxofylline SR 600) and the 400 mg tablet currently available on the market (DOXOBID); Doxofylline SR 650 and Doxofylline SR 600 have been administered once-a-day, whereas DOXOBID has been administered twice a day. Pharmacokinetic parameters have been calculated using KINETICA software. The area under the curve (AUC) was subjected to statistical treatment for 30 significance by one-way analysis of variance ANOVA) using software, Jandel 8 WO 2009/112436 PCT/EP2009/052675 Scientifica, California. The pharmacokinetic parameters calculated using KINETICA Software are shown in figures 1 and 2; more in details, figure 1 shows the data of Doxofylline SR 650 compared to that of DOXOBID whereas figure 2 shows the data of Doxofylline 5 SR 600 compared to that of DOXOBID. The results clearly show that the AUC, which is an indicator of extent of absorption, obtained with Doxofylline SR 650 and Doxofylline SR 600 mg tablets showed non statistically significant differences (p = 0.5482 for Doxofylline SR 650 mg; p = 0.6148 for Doxofylline SR 600 mg) when compared to the AUC obtained with DOXOBID 400 mg twice 10 daily. The relative bioavailabilities (T/R) of the two test formulations were found to be 0.979 ± 0.221 and 0.922 ± 0.41 for Doxofylline SR 650 mg and Doxofylline SR 600 mg tablets, respectively. Excellent results were obtained for Doxofylline SR 650 mg tablets. The bioavailability of doxofylline was found to be about 0.98 and 0.92 times after 15 administration of Doxofylline SR 650 mg and Doxofylline SR 600 mg tablets, respectively. The bioavailability of Doxofylline 650 mg was almost identical to that of DOXOBID 400 mg twice daily, 12 hourly, therefore it could be possible to administer a single dose of Doxofylline SR 650 mg tablet instead of doxofylline 400 mg twice daily to treat symptoms associated with asthma and. COPD (chronic 20 obstructive pulmonary disease). EXAMPLE 5 In the study both sustained release drugs were compared to DOXOBID immediate release tablets, containing doxofylline 400mg for twice daily administration. The open-label bioequivalence study was performed in 24 healthy, adult, male 25 subjects. Each subject received 1 dose of the 650 mg tablet of example 2 (Doxofylline SR 650, herinafter indicated as DOXOTOP) and 2 doses of DOXOBID tablet at 0 and 12 hours. There was a wash-out period of 7 days between each study drug to prevent any carry-over effect. The order of the study drug administrations was randomized for all patients. 30 Doxofylline serum concentrations of DOXOTOP were tested 1 hour before drug administration and post-dose at 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 3.00, 9 WO 2009/112436 PCT/EP2009/052675 4.00, 6.00, 9.00, 12.00, 16.00 and 24.00 hours. At each time point 5 ml of blood was taken from the subject. Because the reference product (DOXOBID) is administered twice daily, the plasma levels should be tested at additional time points in order to measure the plasma peak after the second administration. 5 Therefore twenty-six time points are measured, 1 hour before drug administration and post-dose at 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 3.00, 4.00, 6.00, 9.00, 12.00, 12.25, 12.50, 12.75, 13.00, 13.25, 13.50, 13.75, 14.00, 15.00, 16.00, 18.00, 21.00 and 24.00 hours. At each time point 5 ml of blood was collected from the subject. All blood samples were collected via indwelling cannula placed 10 in the forearm vein. From all the individual serum measurements the mean area under the serum concentration curve from time 0 to the last concentration measured (AUC(0-t)) and from time 0 to infinity (AUC(0-co)) were calculated. The mean maximum serum concentration (Cmax) was also calculated. The results are summarized in 15 table 1. Table 1. Mean (untransformed) results of 24 subjects for all formulations Mean Mean Mean AUC(0- Cmax (ng-h/ml) oc) (ng-h/ml) (ng/ml) DOXOBID (2x400 mg) 1st peak: 2186.595 13993.816 15781.742 p 2 2nd peak: 2828.901 DOXOTOP (650mg) 12892.408 16349.376 1189.503 20 The 90% confidence interval of the mean AUC(0-t), AUC(0-CC) for the log transformed data of DOXOTOP (650mg) compared to DOXOBID (2x400mg) were also calculated in order to assess the bioequivalence for once daily use. The 10 WO 2009/112436 PCT/EP2009/052675 results are summarized in table 2. Table 2. 90% confidence intervals on the log transformed data for the sustained release formulation compared to DOXOBID (400mg twice daily) 90% CI AUC(0-t) 90% CI AUC(0-oc) DOXOTOP (650mg) 81.53-95.71 94.16-111.37 5 According to EMEA (2001) and US FDA (2003) guidelines, bioequivalence is demonstrated if the 90% confidence interval of the AUC falls within an acceptance interval of 80% to 125%. The above results show that for DOXOTOP (650mg) the 90% confidence interval of the AUC(ot) and AUC(o-) lie within the 10 acceptance interval. This bioequivalence study shows that DOXOTOP (650mg) has an equivalent plasma concentration (AUC) of the active compound doxofylline compared to the conventional immediate release tablets administered twice daily. Therefore the efficacy of DOXOTOP is equivalent to that of the immediate release tablets 15 administered twice daily. Furthermore, the doxofylline plasma concentration of DOXOTOP decreases very slowly after the peak concentration, as shown in figure 3. This smooth declining slope ensures a sustained concentration to yield therapeutic effect for the complete 24 hours post-dosing. Additionally, because the maximum peak concentration (Cmax) is significantly lower than that of the 20 conventional tablets, the risk of adverse reactions is expected to be lower, since the patient is exposed to lower levels of active drug. When taking the results of the study into consideration, it can be concluded that a once daily dose of DOXOTOP (650mg) is bioequivalent to DOXOBID 400mg tablets twice daily. This sustained release formulation therefore has an equal 25 efficacy as the conventional tablets, but may have an even better safety profile since the peak serum concentrations are lower and less active drug is administered to the patient on a daily basis. 11

Claims

1. A modified release pharmaceutical composition which comprises as the active ingredient doxofylline, in combination with a polymer chosen from a pharmaceutically acceptable cellulose derivative, a pharmaceutically acceptable 5 methacrylate derivative, their mixtures, and pharmaceutically acceptable salts thereof.

2. The composition as claimed in claim 1, characterised in that the polymer is selected from the pharmaceutically acceptable cellulose esters and ethers.

3. The composition as claimed in claim 2, characterised in that the polymer 10 is a hydroxyalkyl cellulose.

4. The composition as claimed in claim 2, characterised in that the polymer is selected from methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, 15 hydroxypropylmethyl cellulose acetate succinate, their mixtures and salts.

5. The composition as claimed in claim 1, characterised in that the polymer is the copolymer methacrylic acid/methyl methacrylate, the copolymer methacrylic acid/ethyl methacrylate, their mixtures and salts.

6. The composition as claimed in any one of the preceding claims, 20 characterised in that it is in the form of an oral tablet.

7. The composition as claimed in any one of the preceding claims, characterised in that it further comprises one or more components selected from lubricating agents, filling agents, agents aiding compression and their combinations. 25

8. The composition as claimed in any one of the preceding claims, characterised in that it is in dosage units, in the form of a tablet, and that it comprises a quantity of active ingredient between 550 and 800 mg, preferably between 600 and 750 mg.

9. The composition as claimed in claim 8, characterised in that it comprises 30 between 625 and 700 mg of active ingredient.

10. The composition as claimed in claim 8, characterised in that it comprises 12 WO 2009/112436 PCT/EP2009/052675 about 650 mg of active ingredient.

11. The composition as claimed in any one of the preceding claims, characterised in that it comprises between 30 and 200 mg of said polymer, preferably between 120 and 130 mg. 5

12. The composition as claimed in claim 11, characterised in that it further comprises a lubricant and/or a filling agent.

13. The composition as claimed in claim 12, characterised in that said lubricant is magnesium stearate and/or said filling agent is talc and/or microcrystalline cellulose. 10

14. The composition as claimed in claim 12, characterised in that it comprises from I to 15 mg of said lubricant.

15. The composition as claimed in claim 12, characterised in that it comprises from 10 to 200 mg of filling agent, preferably between 100 and 150 mg.

16. The composition as claimed in any one of the preceding claims, which 15 comprises 650 mg of doxofylline, 50 mg of a cellulose ester and/or ether, 30 mg of microcrystalline cellulose and 5 mg of magnesium stearate.

17. The composition as claimed in any one of the preceding claims, which comprises 650 mg of doxofylline, 125 mg of a cellulose ester and/or ether, 100 mg of microcrystalline cellulose, 18 mg of talc and 7 mg of magnesium stearate. 20

18. The composition as claimed in any one of the preceding claims, characterised in that it comprises doxofylline, hydroxyalkyl cellulose, magnesium stearate microcrystalline cellulose and optionally talc.

19. The composition as claimed in any one of the preceding claims, characterised in that it comprises between 625 and 675 mg of doxofylline, 25 between 100 and 150 mg of hydroxypropylmethyl cellulose, between 75 and 125 mg of microcrystalline cellulose, between 15 and 20 mg of talc and between 5 and 10 mg of magnesium stearate.

20. The composition as claimed in any one of the preceding claims, characterised in that it comprises 650 mg of doxofylline, 125 mg of 30 hydroxypropylmethyl cellulose, 100 mg of microcrystalline cellulose, 18 mg of talc and 7 mg of magnesium stearate. 13 WO 2009/112436 PCT/EP2009/052675

21. A process for preparation of the composition according to any one of the preceding claims, in oral tablet form, which comprises: (a) mixing the doxofylline with the polymer and optionally a filling agent; 5 (b) pre-compressing the mixture (a); (c) grinding the mixture compressed in (b); (d) optionally mixing the mixture ground in (c) with the other excipients; (e) compressing the mixture (d). 10

22. A composition as claimed in any one of the claims from 1 to 20, for use in the treatment of asthma and/or chronic obstructive pulmonary disease (COPD).

23. A composition as claimed in claim 22, characterized in that it is administered once a day.

24. A composition as claimed in claim 22, characterized in that it is 15 administered orally.

25. A composition as claimed in claim 22, characterized in that it is administered to a human being.

26. A method for improving bioavailability of doxofylline in a human being, which method comprises administering to said human being a composition 20 according to any one of claims I to 20.

27. A method for obtaining in a human being a plasmatic level bioequivalent to that obtainable by administering twice a day an immediate release composition containing 400 mg of doxofylline, which method comprises administering once a day a composition according to any one of claims 1 to 20. 25

28. A method according to claim 27, characterized in that said immediate release composition has the following quali-quantitative composition: doxofylline 400 mg, colloidal silicon dioxide 13 mg, corn starch 63 mg, mannitol 40 mg, povidone 7 mg, microcrystalline cellulose 64 mg, talc 30 mg, magnesium stearate 3 mg and water 0.08 ml 30 14