MODIFIER SYSTEM FOR COMPOSITIONS CONTAINING LAYERED DOUBLE HYDROXIDE

Abstract

The invention relates to a composition comprising: i) one or more LDH-active anion materials comprising an LDH matrix intercalated with one or more active anions, and ii) a modifier system comprising a) one or more surfactants, in combination with b) one or more compounds having the generic formula MA, where M comprises one or more positively charged ions and A comprises one or more negatively charged counter ions.

Claims

1. A composition comprising: i) one or more layered double hydroxide (LDH)-active anion materials comprising an LDH matrix intercalated with one or more active anions, and ii) a modifier system comprising a) one or more surfactants, in combination with b) one or more compounds having the generic formula MA, where M comprises one or more positively charged ions and A comprises one or more negatively charged counter ions.

2. A composition according to claim 1 wherein the one or more surfactants are selected from anionic surfactants, zwitterionic (amphoteric) surfactants, cationic surfactants and non-ionic surfactants.

3. A composition according to claim 2 wherein the one or more surfactants are selected from sodium lauryl sulfate, lecithin and poloxamer.

4. A composition according to claim 1 wherein M comprises the one or more positively charged ions selected from one or more mono-, di-, or tri-valent metals.

5. A composition according to claim 4 wherein M comprises one or more metals selected from alkali metals, alkaline earth metals and transition metals.

6. A composition according to claim 1 wherein the one or more negatively charged counter ions, A, are selected from carbonate, hydrogen carbonate, sulfate, hydroxide, oxide, chloride, bromide, fluoride, nitrate, dihydrogen phosphate, hydrogen phosphate, phosphate, acetate, maleate, citrate, mesylate, tartrate, gluconate, formate, malate, oxylate, succinate, tosylate, fumarate, pamoate, furoate, propionate, saccharate and thiocyanate anions.

7. A composition according to claim 1 wherein the one or more active anions are derived from ibuprofen, naproxen, ketorolac, diclofenac, indomethacin and atorvastatin, either in salt and/or free acid form.

8. A composition according to claim 1 wherein the modifier system has a weight ratio of the LDH matrix:the one or more compounds having the generic formula MA: the one or more surfactants, of 2:0.1 to 4:0.1 to 4.

9. A composition according to claim 1 comprising 400 mg LDH-ibuprofen (contains 200 mg LDH), at least 100 mg sodium carbonate and 200 mg of one or more surfactants selected from sodium lauryl sulfate, poloxamer and lecithin.

10. (canceled)

11. A formulation comprising a composition containing i) one or more LDH-active anion materials, and ii) a modifier system comprising a) one or more surfactants, in combination with b) one or more compounds having the generic formula MA, where M comprises one or more positively charged ions and A comprises one or more negatively charged counter ions.

12. A formulation according to claim 11 in a form selected from dry granules, tablets, caplets, orally disintegrating tablets, orally disintegrating granules, lozenges, films, capsules, powders, effervescent formulations and buccal and sub-lingual formats.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0053] The present invention will now be described with reference to the following figures in which:

[0054] FIG. 1 is a graph of geometric mean concentration against time to compare the Brufen® single dose PK with that obtained for LDH-ibuprofen.

[0055] FIG. 2 is a graph of % solubility v the amount of sodium carbonate, for sodium lauryl sulfate (SLS) surfactant;

[0056] FIG. 3 is a graph of % solubility v the amount of sodium carbonate, for lecithin surfactant;

[0057] FIG. 4 is a graph of % solubility v the amount of sodium carbonate, for poloxamer 407 surfactant;

[0058] FIG. 5 is a graph of % active anion released v the amount of sodium carbonate, for sodium lauryl sulfate (SLS) surfactant;

[0059] FIG. 6 is a graph of % active anion released v the amount of sodium carbonate, for lecithin surfactant;

[0060] FIG. 7 is a graph of % active anion released v the amount of sodium carbonate, for poloxamer 407;

[0061] FIG. 8 is a bar graph showing % solubility v amount of sodium lauryl sulfate (SLS) surfactant;

[0062] FIG. 9 is a bar graph showing % solubility v amount of lecithin surfactant;

[0063] FIG. 10 is a bar graph showing % solubility v amount of poloxamer 407 surfactant;

[0064] FIG. 11 is a bar graph showing % released v amount of sodium lauryl sulfate (SLS) surfactant;

[0065] FIG. 12 is a bar graph showing % released v amount of lecithin surfactant;

[0066] FIG. 13 is a bar graph showing % released v amount of poloxamer 407 surfactant;

[0067] FIG. 14 is a graph showing the % solubility for 0 mg surfactant v amount of sodium carbonate;

[0068] FIG. 15 is a graph showing % release for 0 mg surfactant v amount of sodium carbonate;

[0069] FIG. 16 is a graph showing the % solubility for 50 mg surfactant v amount of sodium carbonate;

[0070] FIG. 17 is a graph showing % release for 50 mg surfactant v amount of sodium carbonate;

[0071] FIG. 18 is a graph showing the % solubility for 100 mg surfactant v amount of sodium carbonate;

[0072] FIG. 19 is a graph showing % release for 100 mg surfactant v amount of sodium carbonate;

[0073] FIG. 20 is a graph showing the % solubility for 200 mg surfactant v amount of sodium carbonate;

[0074] FIG. 21 is a graph showing % release for 200 mg surfactant v amount of sodium carbonate;

[0075] FIG. 22 is a graph showing pH v % solubility in sodium lauryl sulfate (SLS) with sodium carbonate;

[0076] FIG. 23 is a graph showing pH % release in sodium lauryl sulfate (SLS) with sodium carbonate;

[0077] FIG. 24 is a graph showing pH v % solubility in lecithin with sodium carbonate;

[0078] FIG. 25 is a graph showing pH % release in lecithin with sodium carbonate;

[0079] FIG. 26 is a graph showing pH v % solubility in poloxamer 407 with sodium carbonate;

[0080] FIG. 27 is a graph showing pH % release in poloxamer 407 with sodium carbonate;

[0081] FIG. 28 is a table of the % solubility and % release results obtained in Experiment 4; and

[0082] FIG. 29 is a table of the % solubility and % release results obtained in Experiment 5.

DETAILED DESCRIPTION

Experiment 1—Comparing the In Vitro and In Vivo Rate of Release of 400 mg Ibuprofen from LDH-Ibuprofen Tablet Against the Rate of Release of Ibuprofen from Brufen®

[0083] The in vitro dissolution testing of the rate of release of ibuprofen from a tablet formulation of LDH-ibuprofen (400 mg ibuprofen) compared against rate of release of ibuprofen from Brufen®, a commercially available tablet formulation containing 400 mg ibuprofen, showed comparable release of >95% after 5 minutes.

[0084] However, in a clinical study to compare the Pharmacokinetic (PK) performance of a tablet formulation of LDH-ibuprofen (400 mg ibuprofen) against the performance of Brufen®, a commercially available tablet formulation containing 400 mg ibuprofen, the LDH-ibuprofen tablet failed to show bioequivalence to the Brufen® product. As illustrated in FIG. 1, the PK results show comparable AUC and time to maximum plasma concentration (Tmax). The rapid ibuprofen absorption in the first hour in the stomach for the LDH-ibuprofen tablet is comparable with the rate of absorption for Brufen®. Following this however, a slower more prolonged ibuprofen release from the LDH-ibuprofen tablet is observed as the remaining ibuprofen ion-exchanges out of the LDH matrix as it travels down the GI tract. This results in a C.sub.max for the LDH-ibuprofen tablet being reduced to 65% of that observed with Brufen®.

[0085] The differences between the in vitro and in vivo results may be due to the use of a phosphate buffer in the in vitro dissolution testing which may be promoting ion-exchange. This theory was tested and is apparently confirmed as different release rates are obtained depending on which buffer is used and at what concentration. In addition, dissolution testing using FaSSIF and FeSSIF buffers (maleate buffers which are more reflective of the stomach and intestines) showed that these buffers have insufficient buffering capacity to promote ion exchange and hence slowed down the release of the drug from the LDH matrix.

Experiment 2: Testing Different Agents on LDH-Ibuprofen to Determine their Effect on the Amount of Ibuprofen Dissolved

[0086] Experimental Conditions

[0087] 400 mg LDH-ibuprofen (equivalent to 200 mg ibuprofen) is added to 0.05M hydrochloric acid (50 ml) with various agents to test their effect in any on the rate of ibuprofen release. The mixture is stirred for 15 minutes and then sampled HPLC for analysis.

TABLE-US-00001 TABLE 1 AGENT @ 100 mg AGENT @ 300 mg DISSOLVED DISSOLVED AGENT pH (%) mg/mL pH (%) mg/mL NONE (CONTROL) 2.0 1 0.04 6.1 4 0.14 MgCO.sub.3 2.6 2 0.06 — — — Na(CO.sub.3).sub.2 6.2 8 0.33 — — — NaHCO.sub.3 2.7 2 0.09 — — — CaCO.sub.3 2.5 1 0.05 3.6 2 0.08 Mg(OH).sub.2 2.3 1 0.04 Na.sub.2SO.sub.4 3.3 2 0.08 3.7 1 0.05 Sodium Lauryl Sulfate 4.3 1 0.03 5.3 48 1.91 Ca.sub.3(PO.sub.4).sub.2, 3.2 1 0.04 3.7 1 0.05 CaHPO.sub.4 3.2 1 0.03 3.6 1 0.03

[0088] Looking at the above results, there does not appear to be any linear relationship between pH and solubility, e.g. 100 mg sodium carbonate and 300 mg of magnesium carbonate each give a pH of approximately 6, but sodium carbonate dissolved about 8% ibuprofen, whereas magnesium carbonate only dissolved about 3.5% ibuprofen. Consequently, contrary to the teaching in EP1341556B, the rate of ibuprofen release from the LDH layers is not merely a matter of ensuring that the pH is at a particular level. Also, as the above results demonstrate, the addition of sodium carbonate surprisingly improves the rate of ibuprofen release to a greater extent than would be expected from the results obtained for the carbonates disclosed in EP1341556B. The two calcium phosphate materials, although similar to the chemicals used in a phosphate buffer, gave poor dissolution whereas adding the surface active agent sodium lauryl sulfate dissolved the highest amount of ibuprofen at 47.6%.

[0089] The following two test methods have been developed to test the efficacy of the proposed modifier systems according to the present invention. It is particularly instructive to use the two methods in parallel when the modifier system contains a combination of constituents which alter both the solubility and the release of the ibuprofen:

[0090] 1) Solvent System Method for Determining the Total Amount of Ibuprofen Released from the LDH

[0091] This method determines the total amount of ibuprofen that is released from the LDH matrix.

[0092] Method:

[0093] LDH-ibuprofen (200 mg dose of ibuprofen) and modifier agent (where used, in the amounts shown in Table 2), are added to 0.05M HCl (50 mL) and the resulting solution stirred for 15 minutes. After 15 minutes, methanol (50 mL) followed by a 1:1 mixture of methanol and water (150 mL) are added to the stirred LDH-ibuprofen/HCl solution. A sample is then removed for analysis to determine the total amount of ibuprofen (dissolved and undissolved) which is released into the HCl solution. Further dilution is conducted as required.

[0094] 2) Solubility Method for Determining the Amount of Ibuprofen Dissolved

[0095] The solubility method determines how much of the free ibuprofen dissolves in the acid medium. The medium is designed to reflect the conditions found in a fasted human stomach. The difference between the amount determined by method 1 and the amount determined by method 2 is the amount of ibuprofen which formed as a precipitate.

[0096] LDH-ibuprofen (200 mg dose of ibuprofen) and modifier agent according to the present invention (where used, in the amounts shown below in Table 2), are added to 0.05M HCl (50 mL) and the resulting solution stirred for 15 minutes. After 15 minutes, a sample is taken for analysis to determine the amount of ibuprofen dissolved in the HCl solution. Further dilution is conducted if required with a standard diluent (acetonitrile:water).

TABLE-US-00002 TABLE 2 TOTAL AMOUNT OF IBUPROFEN RELEASED AMOUNT OF IBUPROFEN FROM THE LDH AS DISSOLVED AS DETERMINED USING THE DETERMINED USING THE SAMPLE SOLVENT METHOD SOLUBILITY METHOD Ibuprofen free acid 95% Negligible LDH-ibuprofen + 300 mg 41% 26% Na.sub.2CO.sub.3 LDH-ibuprofen + 300 mg 59% 48% SLS

Experiment 3: Testing Modifier Systems According to the Present Invention which Comprise a Range of Compounds with the General Formula MA Together with a Range of Surfactants

[0097] A composition containing 400 mg LDH-ibuprofen (200 mg dose of ibuprofen), and a modifier system containing 200 mg of a compound with the general formula MA and 200 mg of a surfactant, were mixed together and added to 0.05M HCl (50 mL) and the resulting solution stirred for 15 minutes. Samples of the of the reaction solution were removed and used to determine the amount of ibuprofen released by each of the modifier systems using both the solvent system method and the solubility method described above. The results obtained are detailed below in Table 3a and Table 3b.

TABLE-US-00003 TABLE 3a None Lecithin Poloxamer Sodium lauryl sulfate Solubility Solvent Solubility Solvent Solubility Solvent Solubility Solvent Surfactant Method Method Method Method Method Method Method Method Salt (200 mg) pH (%) (%) pH (%) (%) pH (%) (%) pH (%) (%) None 2.0 1 40 Sodium carbonate 7.4 3 82 9.0 6 56 9.3 57 88 Sodium Bicarbonate 4.9 4 43 Sodium sulfate 2.4 3 56 Sodium nitrate 2.1 4 64 Sodium dihydrogen 3.9 8 22 phosphate Sodium phosphate 7.3 30 99 Sodium hydroxide 12.1 33 63 Sodium chloride 2.8 2 51 Disodium hydrogen 5.8 13 95 phosphate Sodium citrate 4.3 1 95 Magnesium carbonate 2.9 2 44 Aluminium carbonate 2.1 1 11 Calcium carbonate 4.9 0 26 Lithium citrate 5.6 14 94

TABLE-US-00004 TABLE 3b Diotadecyl- dimethylammonium Benzalkonium chloride chloride Surfactant Solubility Solvent Solubility Solvent Salt pH Method Method pH Method Method Sodium carbonate 4.0 7 50 6.7 2 36

[0098] As the results in Table 3a show, all of the modifier systems tested affect (increase or decrease) the total amount of ibuprofen released and/or the amount of ibuprofen dissolved, and using this fact it is possible to design a modifier system which will control the amount of active anion released and control the amount of active anion dissolved in the acidic media of the stomach. The modifier system which significantly increases the total amount of ibuprofen released from LDH-ibuprofen, relative to the total amount of ibuprofen released from LDH-ibuprofen in the absence of a modifier system, comprises 200 mg lecithin and 200 mg of one of sodium carbonate, sodium phosphate, disodium hydrogen phosphate, sodium citrate, lithium carbonate and lithium citrate. A modifier system which comprises 200 mg sodium lauryl sulfate and 200 mg sodium carbonate also significantly increases both the total amount of ibuprofen released and the amount of ibuprofen which dissolves. A modifier system which significantly decreases the total amount of ibuprofen released from LDH-ibuprofen, relative to the total amount of ibuprofen released from LDH-ibuprofen in the absence of a modifier system, comprises 200 mg lecithin and 200 mg of one of sodium dihydrogen phosphate, aluminium carbonate and calcium carbonate.

[0099] Experiment 4: Determination of the Amount of Ibuprofen Released from LDH-Ibuprofen Compositions by the Addition of Test Modifier Systems According to the Present Invention (Sodium Carbonate and Surfactant) to an LDH-Ibuprofen Material.

[0100] A composition containing 400 mg LDH-ibuprofen (200 mg dose of ibuprofen), sodium carbonate and a surfactant in different ratios were mixed together and added to 0.05M HCl (50 mL) and the resulting solution stirred for 15 minutes. Samples of the of the reaction solution were removed and used to determine the amount of ibuprofen released by each of the sodium carbonate/surface active agent combinations using both the solvent system method and the solubility method described above. The results obtained are detailed in FIG. 28.

Conclusion

[0101] The results presented in FIG. 28 highlight many interesting features of the relationship between sodium carbonate and a surfactant, and the resulting effect this combination has on the % release of ibuprofen from an LDH matrix and the % solubility of the released ibuprofen in an acidic medium. Some of these features include:

[0102] The presence of sodium carbonate appears to provide a decrease in the % release of the ibuprofen (41% with sodium carbonate v 65% without sodium carbonate), but the amount of released ibuprofen which then dissolves in an acid medium is increased from 1% (when no sodium carbonate is present) to 25% (when 300 mg sodium carbonate is present).

[0103] For a particular amount of sodium carbonate, the total amount of ibuprofen released does not appear to be influenced by either the choice of surfactant or the amount of surfactant (in the range 50 mg to 300 mg). However, the choice of surfactant does appear to influence the solubility of the released active anion and there is a wide variation in % solubility over the range of surfactants tested. This suggests that not all of the surfactants act to solubilise the released ibuprofen. Also the presence of sodium carbonate appears to act in a similar way with all surfactants because (apart for a couple of exceptions 200 mg Sodium Lauryl Sulfate (SLS) and 200 mg lecithin) the % release is of a similar order of magnitude for a given level of sodium carbonate.

[0104] The addition of <100 mg sodium carbonate appears to cause a decrease in the % release, relative to the % release observed for 0 mg sodium carbonate, whereas the addition of >100 mg sodium carbonate appears to increase % release and with 200 mg sodium carbonate % release of 77 to 88% is observed. This provides the benefit that the amount of ibuprofen release can be controlled, and not just increased, by using the modifier systems of the present invention.

Experiment 5: Determination of the Amount of Active Anion Released from LDH-Active Anion Compositions by the Addition of Test Modifier Systems According to the Present Invention (Sodium Carbonate and Surfactant) to an LDH-Active Anion Material

[0105] This Experiment is analogous to Experiment 4 above except that it tests the effect of the modifier systems according to the present invention (which comprise either lecithin or poloxamer in combination with sodium carbonate) on LDH-active anion materials, where the active anion is either naproxen, ketorolac, diclofenac or atorvastatin.

[0106] A composition containing LDH-active anion (containing a 200 mg dose of the active anion), sodium carbonate and a surfactant in different ratios were mixed together and added to 0.05M HCl (50 mL) and the resulting solution stirred for 15 minutes. Samples of the reaction solution were removed and used to determine the amount of active anion released by each of the sodium carbonate/surface active agent combinations using both the solvent system method and the solubility method described above. The results obtained are detailed in FIG. 29.