URINARY ALKALIZING MEDICINAL AND/OR PHARMACEUTICAL COMPOSITION FOR THE ORAL TREATMENT OF INTERSTITIAL CYSTITIS / BLADDER PAIN SYNDROME (IC/BPS) AND FORMULATION THEREOF

Abstract

The present invention relates to novel medicinal and/or pharmaceutical urinary, extended-release alkalizing composition advantageously a tablet for the oral treatment of interstitial cystitis/bladder pain syndrome (IC/BPS) and/or for general alkalization of the human body for long term where according to the subject matter of the invention the composition is potassium free, the composition has a sustained and/or controlled release dosage form and comprises following components advantageously with certain consistence: Citric acid, Sodium citrate, Magnesium citrate, and comprises following components advantageously with a certain consistence as excipients: Aerosil, Avicel DG, Benecel hypromellose microcrystalline cellulose (HPMC) as grade, advantageously Benecel K100M PH DC HPMC and Magnesium stearate. The subject matter of the present invention relates furthermore to novel medicinal and/or pharmaceutical urinary, extended-release alkalizing composition wherein a single administered dose of the composition achieves a therapeutic alkalizing concentration for providing a neutral pH value of the urine between values of 6.9 to 7.5 advantageously 7.38 in an individual for 12 hours. According to the release kinetics of the active ingredient of the composition the final conclusion is that the sustained and/or controlled release tablet according to the invention provides in vivo constant and continuous therapeutic concentration in case of 2×1 daily dosage. The subject matter of the present invention furthermore relates to the process for the formulation of the composition according to the invention because during the homogenization of the above described active ingredients a special formulation process is needed for avoiding liquefaction and the formation of eutectic.

Claims

1. A medicinal and/or pharmaceutical urinary, extended-release alkalizing composition for the oral treatment of interstitial cystitis/bladder pain syndrome (IC/BPS) by alkalizing the urine and/or for general alkalization of the human body for long term, wherein the alkalizing composition is a sustained and/or controlled release and potassium-free composition, comprising: the following components as active ingredients: citric acid, sodium citrate, and magnesium citrate; and the following components as excipients: Aerosil, Avicel DG, Benecel hypromellose microcrystalline cellulose (HPMC) as grade; and Magnesium stearate.

2. The medicinal and/or pharmaceutical urinary, extended-release alkalizing composition according to claim 1 wherein the composition is a tablet.

3. The medicinal and/or pharmaceutical urinary, extended-release alkalizing composition according to claim 1, wherein the composition is potassium-free.

4. The medicinal and/or pharmaceutical urinary, extended-release alkalizing composition according to claim 1, wherein the composition has a sustained and/or controlled release dosage form.

5. The medicinal and/or pharmaceutical urinary, extended-release alkalizing composition according claim 1, wherein the composition comprises the active ingredients with the following consistence: 50 to 100 mg citric acid and 130 to 250 mg sodium citrate and 190 to 290 mg magnesium citrate.

6. The medicinal and/or pharmaceutical urinary, extended-release alkalizing composition according to claim 5, wherein the composition comprises the active ingredients with the following consistence: 68 mg citric acid and 183 mg sodium citrate and 243 mg magnesium citrate.

7. The medicinal and/or pharmaceutical urinary, extended-release alkalizing composition according to claim 5, wherein the composition comprises the active ingredients with the following consistence: 53.17 mg citric acid and 143.09 mg sodium citrate and 190 mg magnesium citrate.

8. The medicinal and/or pharmaceutical urinary, extended-release alkalizing composition according to claim 1, wherein the composition comprises the excipients with the following consistence in weight percentage: 0.5% Aerosil; 15% to 25% Avicel DG; 15% to 25% Benecel hypromellose microcrystalline cellulose (HPMC) as grade; and 0.5% Magnesium stearate.

9. The medicinal and/or pharmaceutical urinary, extended-release alkalizing composition according to claim 8, wherein the consistence of the following excipients in weight percentage in the composition is the following: 19% Avicel DG; and 20% Benecel hypromellose microcrystalline cellulose (HPMC) as grade.

10. The medicinal and/or pharmaceutical urinary, extended-release alkalizing composition according to claim 1, wherein that the composition comprises Benecel K100M PH DC HPMC as grade.

11. The medicinal and/or pharmaceutical urinary, extended-release alkalizing composition according to claim 1, wherein a single administered dose of the composition achieves a therapeutic alkalizing concentration for providing a neutral pH value of the urine between values of 6.9 to 7.5 in an individual for about 8 to about 14 hours.

12. The medicinal and/or pharmaceutical urinary, extended-release alkalizing composition according to claim 11, wherein a single administered dose of the composition achieves a therapeutic alkalizing concentration for providing a neutral 7.38 pH value of the urine in an individual for 12 hours.

13. A process for the formulation of medicinal and/or pharmaceutical urinary, extended-release alkalizing composition according to claim in tablet form by the following steps for avoiding liquefaction and the formation of eutectic: each active ingredient is pulverized separately until reaching the particle size of 6 fine-mesh sieve; adding the excipient Aerosil with moisture retention capability to each active ingredient separately in small parts by continuous mixing in an amount of totally 0.5%; providing the optimization of the rheological features of the granulates for formulating tablets by adding excipient Avicel DG with high moisture retention capability to each active ingredient separately in small parts by continuous mixing; for providing the sustained and/or controlled release feature, adding Benecel K100M PH DC HPMC grade to each mixtures comprising each active ingredients separately and homogenizing each of the mixture of the components separately; after combining of the three above prepared mixture of the excipients and ingredients and homogenizing the mixture, providing the required lubricant effect by adding excipient Magnesium stearate in an amount of 0.5%, and formulating the granulates prepared by dry granulation into tablets by an excenter type Korsch tablet press machine.

Description

TARGET AND SOLUTION ACCORDING TO THE INVENTION

[0071] Using the traditional urinary alkalizing medicines was proved to be effective for raising the urine pH, but as it was described in the previous chapter, potassium caused the worsening of the symptoms during the process, lowering their efficacy.

[0072] According to the literature for the alkalization of the urine the optimal solution is the use of different citric salts like in case of e.g. Magurlit or Blemaren-N but both medicines contain potassium salts.

[0073] Using NaHCO.sub.3 for urine alkalization is not a good solution because the acid content of the stomach immediately neutralises the effect thereof.

[0074] The citric salts are optimal for alkalizing the urine but because of their quick half period the alkalizing effect passes quickly and the therefore to keep the pH value in the appropriate neutral range the dosage of the normal alkalizing tablets comprising citric salts could be 4-6 tablets or more a day which is very high.

[0075] Using magnesium and sodium salts of citric acid is also optimal because magnesium and sodium are completely eliminating from the human body within 24-48 hours so a danger of a cumulation is excluded.

[0076] Therefore the composition according to the subject matter of the invention [0077] should contain citric acid and different citrate salts, [0078] the composition should be potassium-free and [0079] to avoid pH value fluctuation of the urine the solution should be a sustained and/or controlled release composition advantageously a tablet.

[0080] According to several in vitro tests, a duration of 12 hours is also possible concerning the alkalizing effect of the tablet.

[0081] During this time, the tablet will release the active ingredients sustained and linearly as a controlled-release tablet a determined, nearly constant quantity of the active ingredient was released. [0082] Using the composition according to the invention the urine pH fluctuation of the IC/BPS will be attenuated. [0083] The fact that the tablet has to be taken fewer times and it affects the pH for a prolonged time definitely leads to some attenuation. With or without a considerable fluctuation if the pH remains in the 6.5-7.5 range (thus, it does not make the symptoms worse), the composition according to the invention can inarguably be the optimal alkalizing tablet for the treatment of IC/BPS. [0084] IC/BPS is not the only condition in which the GAG-layer is damaged. There are plenty of urinary tract infections (UTIs) with a symptom of a deficient GAG-layer and/or an abnormally low urine pH. In these cases the composition according to the invention might be administered for symptomatic treatment, as an analgesic drug. Also, long-lasting alkalization might be useful for certain other conditions, too, namely radiation cystitis or chemo-cystitis following BCG or cytostatic drug instillations. [0085] Another disease which could be treated with the alkalizing composition according to the invention is gout. Gout is a common disease which is definitely worth focusing on. As it has been mentioned before, potassium seems to be useful for treating this condition; allopurinol inhibits the production of uric acid. The urine itself, regarding gout, is often stabilized around a pH value of 5. Raising this might help the effect of allopurinol by raising the urine pH, especially in cases, where potassium-containing drugs are contraindicated.

[0086] Based on the above concerning of the preparation of the optimal alkalizing agent for oral treatment of the IC/BPS by controlling the pH of the urine the target of the invention can be solved as follows: [0087] 1) The pH value of the urine should be provided for long term and continuously neutral and the optimal pH value of the urine should be between 6.9 and 7.5 advantageously 7.38. [0088] 2) The composition according to the invention should provide the required continuous neutral pH value of the urine for 24 hours by 2×1 daily oral dosage of a sustained or controlled release composition advantageously tablet where the active ingredient release during this period should be nearly constant. [0089] 3) The composition according to the invention should be potassium ion free, because the potassium is strongly irritating the urethra and bladder of the IC/BPS patients as it is well known from the literature. By using a potassium-free alkalizing tablet the pain and continuous micturition of the patient can be avoided.

[0090] Preparing a sustained, controlled release tablet with the above indication the optimal choice was using Benecel hypromellose microcrystalline cellulose (HPMC), advantageously Benecel K100M PH DC HPMC as grade, because polymers or Carbomer matrix systems cannot be used because of the high Mg.sup.2+ and Na.sup.+ content thereof.

[0091] The osmotic pressure generated by the cations namely would have destroyed the texture of the matrix.

[0092] The HPMC is much more resistant against the osmotic pressure generated by cations and has a high viscosity which is optimal for a formulation of a sustained, controlled release tablet.

[0093] Finding the exact optimal consistence of the controlled release alkalizing tablet was a very important target and the result was found only by careful and detailed investigation of the dissolution of the active ingredient by using HPLC (High Pressure Thin Layer Chromatography) technique.

[0094] There were features of two excipients investigated: [0095] a) The active ingredient components of the composition according to the invention are extremely hygroscopic so because of the liquefaction the optimal quantity of the excipient Avicel DG with moisture retention capability should be examined. [0096] b) Because of finding the optimal active ingredient release of the composition for 12 hours the optimal consistence and quantity of the HPMC grade component by investigating the dissolution, more precisely the dissolution efficacy of the active ingredient by HPLC. [0097] c) The HPLC investigations were implemented depending on the above two parameters.

[0098] During the investigation of the active ingredient release following parameters were used: [0099] 37° C. [0100] 75 turn/minute [0101] 2.4 ml/sample [0102] phosphate puffer: pH 6.8

[0103] Mathematical Analysis of the Drug Release Profiles in HPLC Investigations.

[0104] To compare the individual dissolution data of the two mostly varying 3.3 tablet compositions, similarity or difference factors were calculated, as a model independent approach. Dissolution efficacies were also calculated for the average dissolution data (1).

[00001]$f1=\frac{\underset{j=1}{\overset{n}{.Math.}}.Math.R_j-T_j.Math.}{\underset{j=1}{\overset{n}{.Math.}}{R}_j}\times 100$

where n is the sampling number, Rj and Tj are the percent dissolved of the reference and the test products at each time point j.

f2=50×log{[1+(1/n)Σ.sub.j=1.sup.nw.sub.j|R.sub.j−T.sub.j|.sup.2].sup.−0.5×100}

where wj is an optional weight factor.

[00002]$\mathrm{DE}=\frac{{\int }_0^{t}y\times \mathrm{dt}}{y_{100}\times t}\times 100\%$

where y is the drug percent dissolved at time t.

[0105] For the determination of release kinetics of active ingredient, release data was fitted to zero-order, first-order and Korsmeyer-Peppas model equations in MS Excel.

[00003]$\begin{array}{c}Q=Q_0+k_{0}t\\ Q_t=Q_0\times e^{-k_{1}t}\\ \frac{Q_t}{Q_{\infty }}=k_{kp}{t}^n\end{array}$

where Q is amount of drug release at time t, Q.sub.0 is the initial amount of drug, Q.sub.t is the amount of drug remaining at time t, and where Qt/Q∞ is fraction of drug released at time t. k.sub.0, k.sub.1, and k.sub.kp are the kinetic constants for zero order, first order, and Korsmeyer-Peppas models, respectively and n is the release exponent, indicative of the drug release mechanism. For Korsmeyer-Peppas model, only release data points were used in the analysis up to 60% drug release (2).

[0106] Results of our investigations: [0107] Hausner factor determined by Stampfvolumeter: 1.173 [0108] Carr index: 15.28 [0109] Value of ASTM: 0.992 (according to the t.sub.g=h/r function); [0110] According to the results of the special and general mass-definition all values are corresponding to the Pharmacopoeia specifications; [0111] In case of N=30 tablets the highest difference was 5% which can be maximum±10%

[0112] The kinetics of the active ingredient release is represented in FIG. 1, FIG. 2 and FIG. 3.

[0113] Based on the test results of the dissolution test, we can state that of 28.33% of the API dissolved in 1 hour. Additionally, 54.64% of the API was released in 3 hours. Finally, 80.83% of the API was released to the dissolution media in 6 hours. The result of the dissolution efficacy calculation was 86.40%. When the data of the two mostly varying samples were compared the result of the difference and similarity factor calculations were found to be 4.03 and 64.87, respectively. First order model was to be the best model describing the release of the API from the hydrophilic matrices, R.sup.2=0.9651 and in case of Korsmeyer-Peppas model the value was R.sup.2=0.9226.

[0114] According to the measured rheological values the investigated granulate shows prime flow features and so the granulate is extremely well usable for formulation of a tablet. As it is shown on FIG. 4.sup.37 and according to the release kinetics of the active ingredient of the composition the final conclusion is that the sustained and/or controlled release tablet according to the invention provides in vivo constant and continuous therapeutic concentration in case of 2×1 daily dosage. .sup.371. Vasvari G, Csontos B, Sovany T, Regdon G, Jr., Benyei A, Varadi J, et al. Development and Characterisation of Modified Release Hard Gelatin Capsules, Based on In Situ Lipid Matrix Formation. AAPS Pharm Sci Tech. 2018. doi: 10.1208/s12249-018-1146-5. 2. Costa P, Manuel J, Lobo S. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001; 13(2):123-33. doi: Doi 10.1016/S0928-0987(01)00095

SUMMARY

[0115] The present invention relates to a novel urinary, sustained and/or controlled-release alkalizing tablet for the oral treatment of interstitial cystitis/bladder pain syndrome (IC/BPS) and/or for general alkalization of the human body for long term where according to the subject matter of the invention the composition is potassium free, and comprises citric acid and citric acid salts as active ingredients.

[0116] As the active ingredient components are extremely hygroscopic a special formulation process was needed for formulating the alkalizing tablet using also different excipients with moisture relating capability.

[0117] Using the alkalizing tablet according to the invention following indications can be treated. [0118] 1) The alkalizing tablet is specially suitable for the oral treatment of the IC/BPS, because the pH value of the urine can provided for long term and continuously within the optimal neutral range of pH values between 6.9 and 7.5 advantageously on 7.38. [0119] 2) By using the sustained and/or controlled release composition according to the invention the required continuous neutral pH value of the urine is provided for 24 hours by 2×1 daily oral dosage where the active ingredient release during this period is nearly constant. [0120] 3) As the composition according to the invention is potassium-free, by using this potassium-free alkalizing tablet the pain and continuous micturition of the patient can be avoided. As it is well known from the literature., the potassium namely is strongly irritating the urethra and bladder of the IC/BPS patients [0121] 4) The extended-release alkalizing tablet is suitable for a general alkalization of the human body for long term. Because of the sustained and/or controlled release effect the alkalization of the body can be provided for long term. [0122] The advantages of the general alkalization are well known, but apart from our tablet according to the invention all usual alkalizing composition has a very short effect.

REFERENCES

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