Biodegradable vaginal pharmaceutical systems

Abstract

The invention relates to the vaginal tablet formulation comprising boric acid, probiotic, local anesthetic and bioadhesive excipient as the drug substance for use in the treatment of vaginal infections.

Description

[0001] DESCRIPTION

[0002] BIODEGRADABLE VAGINAL PHARMACEUTICAL SYSTEMS

[0003] Technical Field

[0004] The present invention relates to tablet formulation approaches comprising boric acid as the drug substance for use in the treatment of vaginal infections.

[0005] State of the Art

[0006] Boric acid (BA) is an inorganic acid used safely in the treatment of vaginitis. The long-term safety of boric acid is unknown, but the risk of systemic toxicity due to vaginal administration appears to be minimal following a dose of 1-2 x 600 mg BA capsules per day for up to 2 weeks (Thorley N et al.).

[0007] In patent document EP2684574A1, boric acid is used, not alone but in combinations, for the prevention of vaginal infections and the disruption of vaginal biofilm. This combination can be with EDTA, as well as with different vegetable oils, zinc, gallium, and different drugs (such as metronidazole). In this document, a dosing regimen that varies in the range of 1 to 3 times a day and requires post-treatment prophylactically twice a week is described in different claims regarding the method of administration. However, this document does not mention bioadhesive systems.

[0008] When vaginal formulation patents containing boric acid are reviewed, vaginal effervescent tablet formulations, in which boric acid is used as an excipient, are generally encountered. Due to the fact that the stability of effervescent tablets is more difficult than conventional tablets and their size is large, it makes patient compliance difficult, and it is among the disadvantages of effervescent tablet formulations that have a patent and contain boric acid as an excipient.

[0009] The literature presents vaginal capsules or semi-solid preparations containing boric acid. A commercial product called Canditon® is an ovule type supplement product that is frequently sold both on the internet and in pharmacies and contains boric acid and vegetable oils and excipients, all of which are imported products. This product is not a medicine. There is no treatment indication. It is a completely different product from the invention proposed as both a formulation and a dosage form.

[0010] There is currently no commercial vaginal tablet formulation in the clinic containing boric acid as the drug substance, which constitutes a significant insufficiency in the clinical treatment of vaginal infections. Considering all these, it is seen that the formulation approach developed within the scope of the present invention has original value and offers an innovative approach in this field.

[0011] Brief Description and Objects of the Invention

[0012] The vaginal tablet developed by the present invention contains boric acid, probiotic, at least one local anesthetic and at least one bioadhesive excipient as the drug substance.

[0013] An object of the invention is to increase the effectiveness of boric acid with an adhesive vaginal system, to reduce the frequency of administration and therefore the cost to the patient, and to reduce side effects by performing treatment at a lower dose without the need for combinations.

[0014] Due to the antibacterial effect of boric acid, the treatment is facilitated by preventing the deterioration of the vaginal flora or by supporting it with probiotics if there is an infection due to flora deterioration.

[0015] At the same time, infection-related conditions such as itching and pain are eliminated with local anesthesia, preferably benzocaine.

[0016] In addition, by adding the bioadhesive excipient to the tablet formulation, the duration of the tablet in the vagina is prolonged and thus its effectiveness is expected to be increased. There is a dosage form that adheres to the vaginal mucosa. The most important advantage of the adhesive system is that it stays in the vagina for a longer time after the application, thus reducing the loss of drug substance and reducing the frequency of application. In addition, boric acid used in the clinic at a dose of 600 mg can be effective at lower doses and possible side effects are prevented. With the adhesive dosage form remaining in the vagina for a longer time, the frequency of application is reduced to once a week. This brings an important advantage and difference in terms of dosing.

[0017] The vaginal tablet formulation with these approaches is not yet in use. Thanks to this formulation developed within the scope of the present invention, the treatment of vaginal infections is carried out much faster and the use of tablets as a dosage form increases patient compliance.

[0018] Detailed Description of the Invention

[0019] The invention includes vaginal tablet formulation approaches comprising boric acid as the drug substance for use in the treatment of vaginal infections. There are no vaginal tablets containing boric acid as the drug substance in Tiirkiye, which constitutes a significant insufficiency in the clinical treatment of vaginal infections.

[0020] The tablet formulation of the invention also contains boric acid as the drug substance, as well as the probiotic, at least one local anesthetic and at least one bioadhesive agent.

[0021] It also comprises at least one other excipient, such as a lubricant, filler and / or dispersant.

[0022] In addition to boric acid, the formulation contains a local anesthetic to relieve the feeling of itching and pain in infections, a probiotic to correct the deteriorated vaginal flora due to infection, and a bioadhesive excipient to prolong the duration of the tablet in the vagina and to ensure its adhesion to the mucosal tissue.

[0023] Lactobacillus acidophilus is used as a probiotic in the preferred embodiment of the invention. Lactobacillus crispatus can also be used in alternative embodiments.

[0024] Benzocaine is included in the formulation as a local anesthetic in the preferred embodiment of the invention.

[0025] Hydroxypropyl methylcellulose (HPMC) is used as a bioadhesive in the preferred embodiment of the invention. This substance was preferred because it has a very strong bioadhesive property and is biocompatible. The fact that the substance does not cause irritation on the surface where it adheres has led to its use in this formulation. Carboxymethyl cellulose can be used as a bioadhesive in alternative embodiments of the invention. Carboxymethyl cellulose is a bioadhesive polymer of natural origin that has similar properties. Another bioadhesive agent alternative can be chitosan.

[0026] Microcrystalline cellulose is used as a filler and dispersant in the preferred embodiment of the invention. This is a filler with a direct printing excipient and also acts as a dispersant. Avicel® PH 102 is preferably used as a microcrystalline cellulose. Alternatively, spray-dried lactose or croscarmellose sodium can be used.

[0027] Magnesium stearate is included as a lubricant in the preferred formulation of the invention. Alternative formulations may be calcium stearate, stearic acid, talc, aerosil, colloidal silica.

[0028] The method of obtaining the vaginal tablet within the scope of the present invention is given below: i. Progressively mixed with the drug substances and other excipients (diluent or filler, bioadhesive excipient) except the lubricant, ii. The lubricant was then progressively added to the powder mixture, iii. The powder mixture was compressed by direct compression method, iv. The obtained tablets were controlled.

[0029] Initially, bioadhesive and non-bioadhesive tablet formulations containing boric acid were developed and tablet controls (diameter / thickness / hardness measurements, friability, weight deviation and dispersion test) were performed.

[0030] Boric acid vaginal tablet formulation: o Boric acid o Microcrystalline cellulose (Avicel® PH 102) o Magnesium stearate Mucoadhesive boric acid vaginal tablet formulation: o Boric acid o Hydroxypropyl methylcellulose (HPMC) o Microcrystalline cellulose (Avicel® PH 102) o Magnesium stearate

[0031] TABLET CONTROLS Weight Deviation Control

[0032] For both formulations, all tablets were weighed individually, and the average weight was calculated.

[0033] Table 1. Tablet weights of boric acid vaginal tablet formulations

[0034] Table 2. Tablet weights of mucoadhesive boric acid vaginal tablet formulations

[0035] According to the TF 1974 pharmacopoeia, all tablets were found to be within the weight deviation limits. Diameter / Thickness / Hardness Controls

[0036] Individual diameter, thickness and hardness measurements were made for each tablet.

[0037] Table 3. Diameter, thickness, and hardness measurement results of boric acid vaginal tablet formulations Table 4. Diameter, thickness, and hardness measurement results of mucoadhesive boric acid vaginal tablet formulations

[0038] Friability Test

[0039] For both formulations, 20 tablets were weighed before and after being placed in the freezer and the necessary calculations were made. Table 5. Weights of boric acid vaginal tablet formulations before and after being placed in the freezer

[0040] Table 6. Weights of mucoadhesive boric acid vaginal tablet formulations before and after being placed in the freezer

[0041] The value B should not exceed 1% and the value B in the two formulations is below 1%.

[0042] Dispersion Test

[0043] For both formulations, 6 tablets were studied at 37°C for 15 minutes in an aqueous medium.

[0044] Boric acid vaginal tablet formulation: All tablets were dispersed within 4.32 minutes.

[0045] Mucoadhesive boric acid vaginal tablet formulation: No tablets were dispersed within 15 minutes.

[0046] When the results of the tablet controls were evaluated, it was seen that the mucoadhesive boric acid vaginal tablets containing bioadhesive agents met the optimum conditions and the preparation of the new formulation approach was paved by adding various excipients and probiotics.

[0047] The final and new mucoadhesive tablet formulation developed in line with the results of the tablet controls are given below with the preferred excipients and preferred amounts: o Boric acid (Drug substance) 600 mg o Local anesthetic 10 mg o Probiotic 100 million live bacteria o Bio-resistant excipient 10-80% o Filler and dispersant excipient 5-15% o Lubricant excipient 0.25-5%

[0048] The weight of the last printed tablet of the said final formulation is 750 milligrams.

[0049] Again, although the drug substance is boric acid and its pharmaceutically acceptable salts, it is preferably used in the formulation at a dose of 600 mg.

[0050] Benzocaine is preferably used as a local anesthetic and is also preferably used in an amount of 10 mg.

[0051] As a probiotic, preferably the Lactobacillus acidophilus microorganism is preferably included in the vaginal tablet formulation with 100 million live bacteria.

[0052] Hydroxypropyl methylcellulose is preferably used as a bioadhesive excipient and is also preferably used in a ratio of 10-80% by weight of the formulation.

[0053] Microcrystalline cellulose excipient, which is a filler and also acts as a dispersant, is preferably used in a ratio in the range of 5-15% by weight of the formulation. Avicel® PH 102, which is a commercial microcrystalline cellulose, is preferably used here.

[0054] The lubricant excipient, preferably selected as magnesium stearate, is also preferably included in the vaginal tablet formulation at a rate of 0.25-5% by weight.

[0055] In the invention, containing antibacterial boric acid, containing probiotics to regulate the vaginal flora, containing local anesthetic to relieve itching and irritation, adhered to the vaginal mucosa, and remained in the application area for a long time and the frequency of application was reduced from 1-3 times a day to once a week. There is a new dosage form that has an antibacterial effect by keeping a more effective dose of boric acid at the application site for a longer time without the need for any combination.

Claims

CLAIMS1. A vaginal tablet, characterized in that it comprises the following: boric acid or its pharmaceutically acceptable salts as the drug substance, at least one local anesthetic, at least one probiotic selected from Lactobacillus acidophilus and Lactobacillus crispatus, and at least one bioadhesive excipient selected from the group consisting of hydroxypropyl methylcellulose, carboxymethyl cellulose and chitosan.

2. The vaginal tablet according to claim 1, characterized in that it comprises at least one lubricant excipient.

3. The vaginal tablet according to claim 1, characterized in that it comprises at least one filler and / or dispersant excipient.

4. The vaginal tablet according to claim 1, characterized in that said local anesthetic is benzocaine.

5. The vaginal tablet according to claim 1, characterized in that the said probiotic is Lactobacillus acidophilus.

6. The vaginal tablet according to claim 1, characterized in that said bioadhesive agent is hydroxypropyl methylcellulose.

7. The vaginal tablet according to claim 1 or 2, characterized in that the lubricant excipient is magnesium stearate.

8. The vaginal tablet according to claim 1 or 3, characterized in that the filler and / or dispersant excipient is microcrystalline cellulose.

9. The vaginal tablet according to claim 1, characterized in that it comprises 600 mg of boric acid or pharmaceutically acceptable salts thereof.

10. The vaginal tablet according to claim 1, characterized in that it comprises 10 mg of local anesthetic.

11. The vaginal tablet according to claim 1, 4 or 10, characterized in that it comprises 10 mg of benzocaine.

12. The vaginal tablet according to claim 1 or 6, characterized in that it comprises 10-80% by weight of bioadhesive agent.

13. The vaginal tablet according to claim 1, 6 or 12, characterized in that it comprises 10- 80% by weight of hydroxypropyl methylcellulose.

14. The vaginal tablet according to claim 2 or 7, characterized in that it comprises 0.25- 5% by weight of magnesium stearate.

15. The vaginal tablet according to claim 3 or 8, characterized in that it comprises 5-15% by weight of microcrystalline cellulose.

16. The vaginal tablet according to claim 1, characterized in that it comprises 600 mg of boric acid or its pharmaceutically acceptable salts, 10 mg of benzocaine, 10-80% by weight of hydroxypropyl methylcellulose, 0.25-5% by weight of magnesium stearate, 5-15% by weight of microcrystalline cellulose.

17. The vaginal tablet according to any one of claims above, characterized in that the weight of the tablet is 750 mg.

18. The tablet according to any one of the preceding claims, characterized in that it is compressed by direct compression method.

19. The vaginal tablet according to any one of the preceding claims for use in the treatment of vaginal infection.

20. A method for treating vaginal infection comprising administering a weekly dose of the vaginal tablet according to any one of claims 1-18 to the vagina.

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