Vaginal tablet formulation

Abstract

The present invention relates to pharmaceutical compositions comprising glucono-δ-lactone suitable for use in the treatment of vaginal microbial infections.

Description

[Technical field]

[0001] Technical Field The present invention relates to pharmaceutical compositions suitable for use in the treatment of vaginal microbial infections. [Background technology]

[0002] background The vaginal microbiome is a dynamic system with a complex mixture of various microorganisms in different ratios and amounts, which depends on lactic acid-producing bacteria to maintain a slightly acidic environment (typically pH 3.5-4.5). A sudden change in the vaginal microbiota can increase the vaginal pH, thus creating a more favorable environment for the establishment of vaginal pathogens that grow optimally at a pH above 5. Therefore, an imbalance in the vaginal microbiota can result in vaginal infections, a pathology that affects the majority of women of reproductive age every year.

[0003] Treatments for vaginal infections include vaginal capsules, tablets and creams such as econazole, clomitrazol, miconazole, tioconazole, butoconazole and fluconazole. However, many of the treatments currently on the market are associated with high recurrence of infections, plus a variety of side effects including stomach upset, headaches and rashes. Some treatments cannot be used during pregnancy as they may harm the fetus. Furthermore, resistance to the drugs may develop as the infectious organisms that the antimicrobials are designed to kill become compatible with the drugs. Additionally, many of the treatments are fat-based pharmaceutical pessaries that are not stable at high temperatures.

[0004] One target of antimicrobial agents is biofilms, which are formed by microbial cells that stick together and are surrounded by a self-produced extracellular polymer matrix. Gluconic acid (CAS 526-95-4) has been shown to reduce the presence of biofilms of different Candida species and some strains [WO2017 / 174731, WO2019 / 068862]. Gluconic acid is difficult to produce as a solid crystalline product and is usually supplied as a 50% aqueous solution. While such aqueous solutions can be used to provide liquid pharmaceutical formulations for vaginal administration, such as vaginal creams, vaginal gels, aqueous solutions are less suitable for use in providing solid pharmaceutical formulations for vaginal administration, such as vaginal tablets, vaginal suppositories, or vaginal rings.

[0005] The need for treatment of vaginal infections may arise at home, at work, or while traveling, and therefore the product needs to be able to undergo shaking, clamping, moderate lifting, and be insensitive to temperature changes. Preferably, the product has a shelf life of at least 6 months, or more preferably at least 1 year. The product needs to be easily applied with or without an applicator. If the product is applied without an applicator, it needs to be stable to hold and not slippery or shiny. Touching with a finger should not change the properties of the product. Furthermore, the product needs to expand until it fits properly and stay in place but not scratch. The product should not slide off. Furthermore, the product needs to have an optimal release time for treating the infection. During treatment, the product should not be perceived as sticky or the rest of the product should not slide off. The product should not discolor the fabric or cause greasy stains. The treatment should preferably be odorless and should not interfere with the user's daily activities such as work, sports, etc. Summary of the Invention [Problem to be solved by the invention]

[0006] In summary, current treatment regimens and prevention plans for infections of the genital tract have many limitations and new treatment and prevention alternatives that are safe during pregnancy and have a low risk of resistance development are needed. [Means for solving the problem]

[0007] Gluconic acid is known to reduce the presence of biofilms. However, gluconic acid is difficult to produce as a solid crystalline product, and therefore is less suitable for use in providing solid pharmaceutical formulations for vaginal administration, such as vaginal tablets, vaginal suppositories, or vaginal rings. In aqueous solution, gluconic acid is in equilibrium with glucono-gamma-lactone and glucono-delta-lactone (GDL; CAS 90-8-2). The inventors have found that such GDLs affect biofilm formation of different Candida species and bacteria, suggesting that GDLs themselves act as active compounds. GDLs are solid at room and body temperatures, and are therefore suitable for use as active ingredients in, for example, vaginal tablets, pessaries, vaginal discs or suppositories or vagitory. The inventors have developed solid pharmaceutical formulations comprising GDLs, suitable for use in the treatment of vaginal microbial infections. Effect of the Invention

[0008] In one aspect, the present invention relates to a pharmaceutical composition comprising glucono-δ-lactone (GDL) and hypromellose (HPMC). In a further aspect, the present invention relates to a solid pharmaceutical composition suitable for vaginal administration, said pharmaceutical composition comprising 5-30 wt% glucono-δ-lactone (GDL) and 10-40 wt% hypromellose (HPMC).

[0009] In another aspect, the invention relates to the use of a pharmaceutical composition as defined herein as a medicament, such as in the treatment of a microbial infection. In one embodiment, the microbial infection is a vaginal microbial infection.

[0010] In yet another aspect, the present invention relates to a method for producing a pharmaceutical composition as defined herein. [Brief description of the drawings]

[0011] [Figure 1] Fluid model for dissolving pessaries under physiological conditions. The vaginal fluid model consists of a reservoir with distilled water, a peristaltic pump, a glass column, and a fraction collector. Water is pumped into the glass column at a rate of 0.1 mL per minute. The pessary is encased in an artificial sponge to simulate the vaginal mucosa. The glass column is heated to a core temperature of 35°C. Fluid is collected with a fraction collector set at 60 min per fraction. The pH of each fraction was measured with a pH electrode. [Diagram 2] Results of measurements using a vaginal fluid model (shown in Figure 1) as described in Example 10. Open circles: Formulation A; open squares: Formulation U; open diamonds: Formulation X; filled circles: Formulation V; filled squares: Formulation Z1; filled diamonds: Formulation Z5. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Detailed Description The present invention relates to a pharmaceutical composition comprising glucono-δ-lactone (GDL) as an active pharmaceutical ingredient and an excipient. In one embodiment, the pharmaceutical composition further comprises a gluconate salt. In one embodiment, the pharmaceutical composition further comprises a binder / modified release agent such as HPMC; a filler such as cellulose and / or starch; a flow agent such as silica; and a lubricant such as magnesium stearate.

[0013] In one aspect, the present invention relates to a pharmaceutical composition comprising glucono-δ-lactone (GDL); and hypromellose (HPMC).

[0014] In one aspect, the present invention relates to a pharmaceutical composition comprising glucono-δ-lactone (GDL); gluconate; and hypromellose (HPMC).

[0015] In one embodiment, the present invention relates to a pharmaceutical composition comprising glucono-δ-lactone (GDL); sodium gluconate (NaG); and hypromellose (HPMC).

[0016] In one embodiment, the pharmaceutical composition is a solid composition.

[0017] The term "pharmaceutical composition" is used herein synonymously with the term "pharmaceutical formulation." In one embodiment, the pharmaceutical composition is in the form of a pharmaceutical dosage form. In one embodiment, the pharmaceutical composition of the present invention is a tablet. In one embodiment, the pharmaceutical composition is suitable for vaginal administration, i.e., the pharmaceutical composition is applied intravaginally, such as in the form of a vaginal tablet or pharmaceutical pessary.

[0018] release rate The pharmaceutical composition of the present invention is a sustained release formulation, and the pharmaceutical composition should release GDL over a long period of time. It is essential that the pharmaceutical composition has a specific release profile so that GDL is released in vivo for a long period of time, such as 24 hours or 48 hours. In one embodiment, the pharmaceutical composition should be administered repeatedly. In that case, it is preferable that the active pharmaceutical ingredient is completely released before the next dose is administered. For example, for administration once a day, the active pharmaceutical ingredient is completely released in vivo within 24 hours after administration. For administration every two days, the active pharmaceutical ingredient is completely released in vivo within 48 hours after administration. Therefore, the pharmaceutical formulation of the present invention is designed to have an optimal release time for treating infectious diseases.

[0019] In order to obtain a release profile suitable for the GDL, excipients such as binders, modified release agents, fillers, flow agents and lubricants are carefully selected. In this regard, it is essential that the pharmaceutical composition contains HPMC.

[0020] In one embodiment, the GDL is released in vivo for at least 6 hours, such as at least 12 hours, such as at least 18 hours, such as at least 24 hours, such as at least 36 hours, such as at least 42 hours. In one embodiment, the GDL is released for at least 24 hours, such as at least 36 hours. In one embodiment, the GDL is released for up to 72 hours, such as up to 48 hours, such as up to 36 hours, such as up to 24 hours. In one embodiment, the GDL is released in vivo for about 18-27 hours. In one embodiment, the GDL is released in vivo for about 48 hours. In one embodiment, the amount of released GDL is measured using a fluid model as described in Example 10 herein.

[0021] During the development of this pharmaceutical composition, dissolution rates were measured using the United States Pharmacopeia (USP) dissolution apparatus 2-paddle method (37° C.±0.5° C.) to predict in vivo drug release profiles. See Example 1 for further details.

[0022] For example, to obtain a release profile suitable for GDL in vivo, it was then determined that no more than 60% of the pharmaceutical composition would dissolve within 2 hours using the United States Pharmacopeia (USP) dissolution apparatus 2-paddle method.

[0023] In one aspect, the present invention relates to a solid pharmaceutical composition comprising 5-30 wt % glucono-δ-lactone (GDL); and 10-40 wt % hypromellose (HPMC), wherein 60% or less of the pharmaceutical composition is dissolved within 2 hours using the United States Pharmacopeia (USP) 2-paddle dissolution apparatus method.

[0024] In one embodiment, 40% or less of the pharmaceutical composition is dissolved within the first hour using the USP paddle method described above. In one embodiment, 60% or less, such as 50% or less, such as 40% or less of the pharmaceutical composition is dissolved within the first 2 hours using the USP paddle method. In one embodiment, 80% or less, such as 75% or less, such as 50% or less of the pharmaceutical composition is dissolved within the first 4 hours using the USP paddle method. In one embodiment, 90% or less, such as 85% or less, such as 65% or less of the pharmaceutical composition is dissolved within the first 6 hours using the USP paddle method.

[0025] In one embodiment, at least 40%, such as at least 50%, such as at least 60%, of the pharmaceutical composition is dissolved within the first 4 hours using the USP paddle method described above. In one embodiment, at least 50%, such as at least 70%, such as at least 75%, of the pharmaceutical composition is dissolved within the first 6 hours using the USP paddle method. In one embodiment, at least 60%, such as at least 80%, such as at least 90%, of the pharmaceutical composition is dissolved within the first 6 hours using the USP paddle method.

[0026] In one embodiment, 30-50%, 30-40%, etc. of the pharmaceutical composition is dissolved within the first 2 hours using the USP paddle method. In one embodiment, 40-60%, 40-50%, etc. of the pharmaceutical composition is dissolved within the first 4 hours using the USP paddle method. In one embodiment, 50-70%, 55-65%, etc. of the pharmaceutical composition is dissolved within the first 6 hours using the USP paddle method. In one embodiment, 60-80%, 65-75%, etc. of the pharmaceutical composition is dissolved within the first 8 hours using the USP paddle method. In one embodiment, 30-50% of the pharmaceutical composition is dissolved within the first 2 hours using the USP paddle method; 40-60% of the pharmaceutical composition is dissolved within the first 4 hours; 50-70% of the pharmaceutical composition is dissolved within the first 6 hours; 60-80% of the pharmaceutical composition is dissolved within the first 8 hours. In one embodiment, a pharmaceutical composition having such a dissolution rate profile is suitable for administration every other day.

[0027] In one embodiment, 30-50%, 35-45%, etc. of the pharmaceutical composition is dissolved within the first 2 hours using the USP paddle method. In one embodiment, 50-70%, 55-65%, etc. of the pharmaceutical composition is dissolved within the first 4 hours using the USP paddle method. In one embodiment, 70-90%, 75-85%, etc. of the pharmaceutical composition is dissolved within the first 6 hours using the USP paddle method. In one embodiment, 80-95%, 85-95%, etc. of the pharmaceutical composition is dissolved within the first 8 hours using the USP paddle method. In one embodiment, 35-45% of the pharmaceutical composition is dissolved within the first 2 hours using the USP paddle method; 50-70% of the pharmaceutical composition is dissolved within the first 4 hours; 70-90% of the pharmaceutical composition is dissolved within the first 6 hours; 80-95% of the pharmaceutical composition is dissolved within the first 8 hours. In one embodiment, a pharmaceutical composition having such a dissolution rate profile is suitable for once-daily administration.

[0028] Glucono-δ-lactone (GDL) The pharmaceutical composition of the present invention comprises glucono-δ-lactone (GDL), CAS number 90-8-2. Glucono-δ-lactone is solid at room temperature and body temperature and is therefore suitable for use as an active ingredient in, for example, vaginal tablets. In one embodiment, the only active pharmaceutical ingredient of the pharmaceutical composition is GDL.

[0029] In one embodiment, the pharmaceutical composition comprises at least 5 wt% GDL, such as at least 10 wt%, such as at least 15 wt%, such as at least 20 wt% GDL. In one embodiment, the pharmaceutical composition comprises 50 wt% or less GDL, such as 40 wt% or less, such as 35 wt% or less, such as 30 wt% or less, such as 25 wt% or less, such as 20 wt% or less GDL. In one embodiment, the pharmaceutical composition comprises 10-30 wt% GDL, such as 10-25 wt%, such as 15-25 wt% GDL, such as about 20 wt% GDL, such as about 15 wt%.

[0030] Gluconate In some embodiments, the pharmaceutical composition of the present invention comprises gluconate, which has a buffering effect that preferably results in a pH value of about 4, such as in the range of 3.6 and 4.2, more specifically about 3.86. In one embodiment, the pH value is measured in the settings described in Example 8. The ratio of GDL to gluconate can be selected to provide a suitable pH, such as 3.5 to 4.5. In one embodiment, the molar ratio of GDL to gluconate in the pharmaceutical composition is about 1:1, such as 2:1 to 1:2, 3:2 to 2:3, etc.

[0031] In one embodiment, the gluconate is selected from the group consisting of sodium gluconate, potassium gluconate, calcium gluconate, magnesium gluconate, iron(II) gluconate, copper(II) gluconate, and zinc gluconate. In one embodiment, the gluconate is sodium gluconate (NaG). Thus, in one embodiment, NaG in the pharmaceutical composition is replaced with an equimolar amount of another gluconate, such as potassium gluconate, calcium gluconate, magnesium gluconate, iron(II) gluconate, copper(II) gluconate, and zinc gluconate.

[0032] In one embodiment, the pharmaceutical composition comprises gluconate in a concentration equivalent to at least an equimolar concentration of NaG, such as 10 wt% NaG, at least 15 wt% NaG, such as at least 15 wt%, such as at least 20 wt%. In one embodiment, the pharmaceutical composition comprises a concentration of gluconate equivalent to an equimolar concentration of NaG of 30 wt% or less, such as 20 wt% NaG or less, such as 25 wt% or less. In one embodiment, the pharmaceutical composition comprises a concentration of gluconate equivalent to an equimolar concentration of NaG of 10-30 wt%, such as 18-19 wt%, such as 15-25 wt%, such as 20-25 wt%, such as 24-25 wt% NaG.

[0033] In one embodiment, the pharmaceutical composition comprises at least 10 wt% NaG, such as at least 15 wt% NaG, such as at least 15 wt%, such as at least 20 wt% NaG. In one embodiment, the pharmaceutical composition comprises 30 wt% or less NaG, such as 20 wt% or less NaG, such as 25 wt% or less NaG. In one embodiment, the pharmaceutical composition comprises 10-30 wt% NaG, such as 18-19 wt%, such as 15-25 wt%, such as 20-25 wt%, such as 24-25 wt% NaG.

[0034] Hypromellose (HPMC) The pharmaceutical composition of the present invention comprises at least one hypromellose (HPMC) component. The HPMC component acts as a release modifier in the pharmaceutical composition. As used herein, the term "hypromellose" refers to hydroxypropyl methylcellulose, CAS number 9004-65-3, E number E464. HPMC is a partially O-methylated and O-(2-hydroxypropylated) cellulose, available in several grades with different molecular weights and degrees of substitution, and therefore different viscosities. HPMC types can be classified based on the degree of substitution, and are therefore given a four-digit number. The first two digits refer to the percentage of methoxy (w / w) and the next two digits refer to the percentage of hydroxypropoxy groups in the dry matter. In one embodiment, the HPMC component of the present invention is selected from the group consisting of HPMC substituted types 2208 (also referred to as "K"), 2910 (also referred to as "E"), 1828 and 2906 (also referred to as "F"). In one embodiment, the HPMC component is substituted type 2208 or 2910.

[0035] The structure of HPMC, including the degree and extent of substitution, produces the viscoelastic properties. In addition to the substitution pattern, different HPMC grades can be distinguished by their apparent viscosity (mPas) of a 2% (w / w) aqueous solution. In one embodiment, the HPMC component has a viscosity of at least 10 mPas, such as at least 15 mPas, such as at least 20 mPas, such as at least 25 mPas, such as at least 30 mPas, such as at least 35 mPas, such as at least 40 mPas, such as at least 45 mPas, such as at least 50 mPas, such as at least 55 mPas, such as at least 60 mPas, such as at least 65 mPas, such as at least 70 mPas, such as at least 75 mPas. In one embodiment, the HPMC component has a viscosity of at least 50 mPas. In one embodiment, the HPMC component has a viscosity of 400.000 mPas or less, such as 300.000 mPas or less, such as 200.000 mPas or less, such as 150.000 mPas or less, such as 100.000 mPas or less, such as 50.000 mPas or less, such as 10.000 mPas or less, such as 1.000 mPas or less, such as 500 mPas or less, such as 250 mPas or less. In one embodiment, the HPMC component has a viscosity in the range of 80 to 280.000 mPas, such as in the range of 80 to 120 mPas, such as in the range of 2.600 to 5.000 mPas, or such as in the range of 150.000 to 280.000 mPas. In one embodiment, the HPMC component has a viscosity of about 100.000 mPas. In one embodiment, the HPMC component has a viscosity of about 200.000 mPas. In one embodiment, the HPMC component has a viscosity of about 4000 mPas. In one embodiment, the HPMC component has a viscosity of about 100 mPas. In one embodiment, the HPMC component has a viscosity of about 15 mPas.

[0036] The HPMC component may be selected from the group consisting of Methocel K100, Methocel K4M and Methocel K200M.

[0037] In one embodiment, the pharmaceutical composition comprises at least 5 wt% HPMC, such as at least 10 wt%, such as at least 10 wt%, such as at least 15 wt%, at least 20 wt%, at least 25 wt%, at least 30 wt%, such as at least 35 wt%, such as at least 40 wt%, such as at least 45 wt%, such as at least 50 wt% HPMC. In one embodiment, the pharmaceutical product comprises no more than 60 wt% HPMC, such as no more than 55 wt%, such as no more than 50 wt%, such as no more than 45 wt%, such as no more than 45 wt%, such as no more than 40 wt%, such as no more than 35 wt%, such as no more than 30 wt%, such as no more than 25 wt%, such as no more than 20 wt%, such as no more than 15 wt%, such as no more than 10 wt% HPMC. In one embodiment, the pharmaceutical composition comprises HPMC in the range of 5-60 wt%, such as 15-40 wt%, such as 5-25 wt%, such as 10-20 wt%, such as 10-40 wt%, such as 20-35% wt%, such as 30-40 wt%. In one embodiment, the pharmaceutical composition comprises HPMC in the range of 5-30 wt%, such as 10-20 wt%, such as about 15 wt% HPMC. In one embodiment, the pharmaceutical composition comprises HPMC in the range of 25-45 wt%, such as 30-30 wt%, such as about 35.5 wt%.

[0038] silica In some embodiments, the pharmaceutical composition further comprises silica. The silica may be selected from the group consisting of colloidal anhydrous silica, colloidal silicone dioxide, colloidal hydrated silica, and hydrophobic colloidal silica. In one embodiment, the silica is colloidal silica. In one embodiment, the silica is 175-225 μm. 2 / g, approx. 200m 2 / g and / or an average primary particle size of 12 nm. In one embodiment, the silica has a pH value of 3.7 to 4.5 in a 4% dispersion. In one embodiment, the silica is Aerosil 200.

[0039] In one embodiment, the pharmaceutical composition comprises 0.1-5 wt% silica, such as 0.1-2 wt%, such as 0.3-0.6 wt%, such as about 0.5 wt%, such as about 0.38 wt% silica.

[0040] Lubricants In some embodiments, the pharmaceutical composition further comprises a lubricant, which can be selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, sucrose palmitate, and sucrose stearate. In one embodiment, the lubricant is magnesium stearate.

[0041] In one embodiment, the pharmaceutical composition comprises 0.1-5 wt% of lubricant, such as 0.1-2 wt%, such as 0.70-1.3 wt%, such as about 1 wt%, such as about 0.75 wt%, such as about 0.38 wt% of lubricant.

[0042] Starch In some embodiments, the pharmaceutical composition further comprises a starch. In one embodiment, the starch is a pregelatinized starch. In one embodiment, the starch is a partially pregelatinized corn starch. In one embodiment, the starch comprises amylopectin and amylose, such as in a 3:1 ratio. The gelatinization level of the starch may be about 20%. The particle size of the starch may be about 65 microns. In one embodiment, the starch is Starch 1500®.

[0043] In one embodiment, the pharmaceutical composition comprises at least 10 wt% starch, such as at least 15 wt%, such as at least 20 wt%, such as at least 30 wt%, such as at least 40 wt%. In one embodiment, the pharmaceutical composition comprises no more than 45 wt% starch, such as no more than 40 wt%, such as no more than 35 wt%, such as no more than 30 wt%, such as no more than 25 wt%, such as no more than 20 wt%. In one embodiment, the pharmaceutical composition comprises 10-50 wt% starch, such as 10-30 wt%, 10-25 wt%, such as 10-20 wt%, such as about 19 wt%, such as about 14.25 wt% starch.

[0044] cellulose In some embodiments, the pharmaceutical composition further comprises cellulose. The cellulose can be selected from the group consisting of microcrystalline cellulose (MCC), siliconized microcrystalline cellulose, and powdered cellulose. In one embodiment, the cellulose is MCC. In one embodiment, the MCC has a nominal particle size of at least 20 μm, such as at least 50 μm, such as at least 75 μm, such as at least 100 μm, such as at least 125 μm, such as at least 140 μm, such as at least 150 μm, such as at least 160 μm. In one embodiment, the MCC has a nominal particle size of 200 μm or less, such as 190 μm or less, such as 180 μm or less, such as 170 μm or less, such as 160 μm or less. In one embodiment, the MCC has a nominal particle size in the range of 140 to 200 μm, such as about 150 to about 180 μm.

[0045] In one embodiment, the pharmaceutical composition comprises at least 20 wt% cellulose, such as at least 30 wt%, such as at least 40 wt%, such as at least 50 wt% cellulose. In one embodiment, the pharmaceutical composition comprises no more than 60 wt% cellulose, such as no more than 50 wt%, such as no more than 40 wt%, such as no more than 30 wt% cellulose. In one embodiment, the pharmaceutical product comprises 20-60 wt% cellulose, such as 20-30 wt%, such as 40-60 wt%, such as 50-60 wt%, such as 30-40 wt%, such as 35-40 wt%, such as about 36 wt% cellulose.

[0046] Lactose and sugar alcohols In some embodiments, the pharmaceutical composition further comprises lactose or a sugar alcohol. In one embodiment, the lactose or sugar alcohol is in the form of a monohydrate. In one embodiment, the sugar alcohol is mannitol. In one embodiment, the lactose is α-lactose.

[0047] In one embodiment, the pharmaceutical composition comprises 40-70 wt% lactose or sugar alcohol, such as 50-60 wt% lactose or sugar alcohol.

[0048] Pharmaceutical Compositions The amounts of the various components of the pharmaceutical composition may be given in wt% in this disclosure. In such cases, the sum of the wt% of the components does not exceed 100 wt%. In some embodiments, the pharmaceutical composition of the present invention comprises or consists of GDL, gluconate, HPMC, starch, silica, and magnesium stearate. In one embodiment, the pharmaceutical composition comprises or consists of 10-25 wt% GDL; 15-30 wt% NaG; 10-40 wt% HPMC; 10-25 wt% starch; 0.25-1.25 wt% silica; and 0.5-1.5 wt% magnesium stearate.

[0049] In one embodiment, the pharmaceutical composition comprises or consists of 10-25 wt% GDL, 15-30 wt% NaG, 30-40 wt% HPMC, 15-45 wt% starch, 0.25-1.25 wt% silica, and 0.5-1.5 wt% magnesium stearate. In one embodiment, the pharmaceutical composition comprises or consists of 15-25 wt% GDL, 20-30 wt% NaG, 30-40 wt% HPMC, 15-25 wt% starch, 0.25-1.25 wt% silica, and 0.5-1.5 wt% magnesium stearate.

[0050] In one embodiment, the pharmaceutical composition comprises or consists essentially of about 20 wt% GDL; 24.5 wt% NaG; 35.5 wt% HPMC; 19 wt% starch; 0.5 wt% silica; and 1 wt% magnesium stearate. In one embodiment, the HPMC is of the 100.000 mPas viscosity type and / or has a degree of substitution of 2208.

[0051] In one embodiment, the pharmaceutical composition comprises or consists essentially of about 20 wt% GDL; 24.1 wt% NaG; 30 wt% HPMC; 24.4 wt% starch; 0.5 wt% silica; and 1 wt% magnesium stearate. In another embodiment, the pharmaceutical composition comprises or consists essentially of about 20 wt% GDL; 24.1 wt% NaG; 35 wt% HPMC; 19.4 wt% starch; 0.5 wt% silica; and 1 wt% magnesium stearate. In another embodiment, the pharmaceutical composition comprises or consists essentially of about 20 wt% GDL; 24.5 wt% NaG; 35 wt% HPMC; 19 wt% starch; 0.5 wt% silica; and 1 wt% magnesium stearate. In another embodiment, the pharmaceutical composition comprises or consists essentially of about 20 wt% GDL; 24.5 wt% NaG; 35 wt% HPMC; 19.25 wt% starch; 0.5 wt% silica; and 0.75 wt% magnesium stearate. In another embodiment, the pharmaceutical composition comprises or consists essentially of about 20 wt% GDL; 24.5 wt% NaG; 35 wt% HPMC; 18.75 wt% starch; 0.5 wt% silica; and 1.25 wt% magnesium stearate. In another embodiment, the pharmaceutical composition comprises or consists essentially of about 20 wt% GDL; 24.5 wt% NaG; 35 wt% HPMC; 19 wt% starch; 0.5 wt% silica; and 1 wt% magnesium stearate. In another embodiment, the pharmaceutical composition comprises or consists essentially of about 10 wt% GDL; 12.25 wt% NaG; 35 wt% HPMC; 41.5 wt% starch; 0.5 wt% silica; and 1.25 wt% magnesium stearate. In another embodiment, the pharmaceutical composition comprises or consists essentially of about 10 wt% GDL; 12.25 wt% NaG; 35 wt% HPMC; 41.5 wt% starch; 0.5 wt% silica; and 0.75 wt% magnesium stearate.In another embodiment, the pharmaceutical composition comprises or consists essentially of about 15 wt% GDL; 18.375 wt% NaG; 35 wt% HPMC; 30.125 wt% starch; 0.5 wt% silica; and 1 wt% magnesium stearate.

[0052] In yet another embodiment, the pharmaceutical composition of the invention comprises or consists of GDL, gluconate, HPMC, silica and magnesium stearate. In one embodiment, the pharmaceutical composition comprises or consists essentially of 15-25 wt% GDL; 20-30 wt% NaG; 45-65 wt% HPMC; 0.25-1.25 wt% silica; and 0.5-1.5 wt% magnesium stearate. In one embodiment, the pharmaceutical composition comprises or consists essentially of about 20 wt% GDL; 24.1 wt% NaG; 54.4 wt% HPMC; 0.5 wt% silica; and 1 wt% magnesium stearate.

[0053] In yet another embodiment, the pharmaceutical composition of the invention comprises or consists of GDL, gluconate, HPMC, MCC, silica and magnesium stearate. In one embodiment, the pharmaceutical composition comprises or consists essentially of 15-25 wt% GDL; 20-30 wt% NaG; 25-40 wt% HPMC; 10-30 wt% MCC; 0.25-1.25 wt% silica; and 0.5-1.5 wt% magnesium stearate. In one embodiment, the pharmaceutical composition comprises or consists essentially of about 20 wt% GDL; 24.1 wt% NaG; 30 wt% HPMC; 24.4 wt% MCC; 0.5 wt% silica; and 1 wt% magnesium stearate.

[0054] In yet another embodiment, the pharmaceutical composition of the present invention comprises or consists of GDL, gluconate, HPMC, MCC, starch, silica and magnesium stearate. In one embodiment, the pharmaceutical composition comprises or consists of 10-25 wt% GDL; 10-30 wt% NaG; 5-40 wt% HPMC; 10-45 wt% MCC; 10-20 wt% starch; 0.25-1.25 wt% silica; and 0.5-1.5 wt% magnesium stearate. In one embodiment, the pharmaceutical composition comprises or consists of 10-20 wt% GDL; 10-25 wt% NaG; 5-25 wt% HPMC; 15-45 wt% MCC; 10-20 wt% starch; 0.25-1.25 wt% silica; and 0.5-1.5 wt% magnesium stearate. In one embodiment, the pharmaceutical composition comprises or consists essentially of about 15 wt% GDL; 18.4 wt% NaG; 15 wt% HPMC; 36 wt% MCC; 14.25 wt% starch; 0.38 wt% silica; and 1.0 wt% magnesium stearate. In one embodiment, the pharmaceutical composition comprises or consists essentially of about 15 wt% GDL; 18.4 wt% NaG; 20 wt% HPMC; 31.25 wt% MCC; 14.25 wt% starch; 0.38 wt% silica; and 0.75 wt% magnesium stearate. In one embodiment, the pharmaceutical composition comprises or consists essentially of about 15 wt% GDL, 18.4 wt% NaG, 10 wt% HPMC, 41.25 wt% MCC, 14.25 wt% starch, 0.38 wt% silica, and 0.75 wt% magnesium stearate. In one embodiment, the HPMC is of the 100 mPas viscosity type.

[0055] In one embodiment, the pharmaceutical composition does not comprise an additional antifungal agent, such as an antifungal agent selected from the group consisting of miconazole, terconazole, isoconazole, fenticonazole, fluconazole, nystatin, ketoconazole, clotrimazole, butoconazole, econazole, tioconazole, itraconazole, 5-fluoracil, and metronidazole.

[0056] Physical properties of the dosage form In one embodiment, the pharmaceutical composition is in the form of a solid dosage form, such as a dosage form such as a tablet. In one embodiment, the mass of the dosage form is at least 0.5 g, such as at least 0.7 g, such as at least 0.85 g, such as at least 1.0 g, such as at least 1.25 g, such as at least 1.4 g. In one embodiment, the mass of the dosage form is 2.0 g or less, such as 1.75 g or less, such as 1.5 g or less, such as 1.0 g or less, such as 0.9 g or less. In one embodiment, the mass of the dosage form is in the range of 0.5 to 2.0 g, such as in the range of 1.4 to 1.6 g, such as in the range of 0.7 to 1.75 g. In one embodiment, the mass of the dosage form is about 1.5 g. In one embodiment, the mass of the dosage form is in the range of 0.5 to 2.0 g, such as in the range of 0.7 to 1.0 g, such as in the range of 0.5 to 1.25 g. In one embodiment, the mass of the dosage form is about 0.85 g. In one embodiment, the mass of the dosage form is about 1.0 g.

[0057] In one embodiment, the dosage form is bullet-shaped.

[0058] In one embodiment, the dosage form has a width of at least 5 mm, such as at least 7 mm, such as at least 9 mm, such as at least 10 mm. In one embodiment, the dosage form has a width of 10 mm or less, such as 15 mm or less, such as 12 mm or less, such as 11 mm or less. In one embodiment, the dosage form has a width in the range of 8 to 12 mm, such as 10 to 10.5 mm, such as 8.5 to 11 mm. In one embodiment, the dosage form has a width in the range of 7.0 to 12 mm, such as 8.5 to 9.5 mm, such as 8.0 to 10 mm. In one embodiment, the dosage form has a width in the range of 10 to 10.5 mm or 8.5 to 9.5 mm.

[0059] In one embodiment, the dosage form has a length of at least 10 mm, such as at least 15 mm, such as at least 20 mm. In one embodiment, the dosage form has a length of 20 mm or less, such as 30 mm or less, such as 25 mm or less. In one embodiment, the dosage form has a length in the range of 10-30 mm, such as in the range of 16-18 mm, such as in the range of 15-20 mm. In one embodiment, the dosage form has a length in the range of 10-30 mm, such as in the range of 22-27 mm, such as in the range of 24-25 mm. In one embodiment, the dosage form has a length in the range of 16-18 mm or 24-25 mm.

[0060] In one embodiment, the dosage form has a width in the range of 10-10.5 mm and a length of 24-25 mm. In another embodiment, the dosage form has a width in the range of 8.5-9.5 mm and a length of 16-18 mm. In another embodiment, the dosage form has a width in the range of 10.0-10.5 mm and a length of 16-18 mm.

[0061] In one embodiment, the amount of GDL in the dosage form is 50-500 mg, such as 100-400 mg, such as 250-350 mg, such as about 300 mg or about 150 mg.

[0062] In one embodiment, the breaking force of the pharmaceutical composition is in the range of 5-25 kp, such as 5-15 kp or 15-25 kp.

[0063] In one embodiment, the lability of the pharmaceutical composition is in the range of 0.01-1%, such as 0.01-0.5%, such as 0.2-0.5%.

[0064] As demonstrated in Example 11 herein, the pharmaceutical compositions disclosed herein are stable for at least 6 months at 25° C. and 40° C. In one embodiment, the pharmaceutical compositions are stable for at least 6 months at 25° C., at least 6 months at 40° C., etc.

[0065] Kit of parts In one aspect, the present invention relates to a kit-of-parts comprising the pharmaceutical composition disclosed herein and an applicator. In one embodiment, the kit-of-parts further comprises instructions.

[0066] Medical Use In one embodiment, the pharmaceutical composition of the present invention is for use as a medicament. In a further embodiment, the pharmaceutical composition is for use in the treatment of a microbial infection. As used herein, the term "treatment" refers to the treatment, prevention and / or alleviation of one or more symptoms.

[0067] As demonstrated in Examples 13 and 14, the pharmaceutical compositions disclosed herein do not cause irritation to the vaginal mucosa and do not cause responses identified as sensitization. The pharmaceutical compositions disclosed herein are suitable for medical use.

[0068] In some embodiments, the microbial infection is a vaginal urogenital infection. In a preferred embodiment, the microbial infection is a vaginal infection. In one embodiment, the microbial infection is selected from the group consisting of fungal infections, bacterial infections, and mixed fungal and bacterial infections. In one embodiment, the microbial infection is vaginal candidiasis as classified as B37.3 of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) by the World Health Organization. Vaginal candidiasis is characterized by the presence of Candida species, most frequently Candida albicans. GDL has been shown in preclinical studies to produce a significant reduction in Candida albicans present in hyphae, i.e., the pathogenic form [WO2017 / 174731]. This hyphae form has the ability to induce inflammation mediated by candidalisin, a cytotoxic peptide toxin that invades tissues and destroys vaginal epithelial cells, and to form biofilms, i.e., complex three-dimensional structures of pathogens and other pathogen cells that bind to cell walls. It has been shown that biofilm formation is necessary for vulvovaginal candidiasis, and that biofilm formation in Candida albicans and other Candida species can be significantly reduced by GDL.

[0069] In some embodiments, the microbial infection is a fungal infection. In one embodiment, the fungal infection is a mycosis, such mycosis being candidiasis. In one embodiment, the candidiasis is vulvar and vaginal candidiasis or urogenital candidiasis. In one embodiment, the fungal infection is caused by Candida albicans, Candida krusei, Candida glabrata, Candida tropicalis, Trichophyton verrucosum, Trichophyton rubrum, Trichophyton violaceum, Trichophyton tonsurans, Microsporum canis, Malassezia and / or Aspergillus.

[0070] In some embodiments, the microbial infection is a bacterial infection. In preclinical studies, GDL has been demonstrated to be useful in treating bacterial infections [WO2019 / 068862]. In one embodiment, the bacterial infection is bacterial vaginosis. In one embodiment, the bacterial infection is caused by Gardnerella vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Treponema pallidum (syphilis), Atopobium vaginae, Prevotella spp., Mobiluncus spp., Peptostreptococcus spp., Porphyromonas spp., Mycoplasma hominis, Bacteroides spp., Ureaplasma urealyticum, Streptococcus, Enterobacteriaceae, Enterococcus, Staphylococcus, Propionibacterium, Escherichia coli, Klebsiella, Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumanii, Streptococcus pyogenes, Streptococcus agalactiae, β-hemolytic streptococci groups C and G, and / or Porphyromonas gingivalis.

[0071] In one embodiment, the infection is an infection in a mammal. In one embodiment, the mammal is a human. Preferably, the mammal is a female. In one embodiment, the female is pregnant. In some embodiments, the pregnancy is low risk. In some embodiments, the pregnancy is high risk. In one embodiment, the high risk pregnancy is at risk for preterm birth as defined by prior preterm birth, short cervical length, presence of biomarkers, or other indications.

[0072] When used in the treatment of vaginal microbial infections, the pharmaceutical composition has pH lowering and biofilm inhibiting properties.

[0073] Manufacturing method In one aspect, the present invention relates to a method for producing a pharmaceutical composition as defined herein, the method comprising the steps of: a. Sifting GDL, gluconate (such as NaG), and HPMC; mixing the sieved ingredients of ba; and The process of compressing the powder mixture of cb into tablets. Includes.

[0074] In one embodiment, the method further comprises the steps of mixing the sieved components of step a with the sieved silica, and adding a lubricant which is premixed with a portion of the mixture produced in step b, i.e., the method comprises: a. Sifting GDL, gluconate (such as NaG), and HPMC; mixing the sieved components of ba with the sieved silica; mixing a portion of the cb mixture with a lubricant; adding and mixing the mixture of (d) and (c) to the remaining mixture of (b); and e. compressing the formed powder mixture of d into tablets. Includes.

[0075] Importantly, the lubricants, such as magnesium stearate, are added at a later stage than the other ingredients, as long mixing times had an adverse effect on the tablet properties.

[0076] In one embodiment, the breaking force for the formed tablets is at least 10 kp.

[0077] In one embodiment, tablets are produced by direct compression with a 10.3 x 24.45 mm punch / die set.

[0078] In one embodiment, the formed tablet is bullet-shaped with a width in the range of 8-12 mm, such as 10-10.5 mm, such as 9-11 mm, and a length in the range of 15-30 mm, such as 24-25 mm, such as 22-27 mm, such as 20-30 mm. In one embodiment, the formed tablet has a mass of about 1.5 g. In one embodiment, the formed tablet is bullet-shaped with a width in the range of 9-13 mm, a length in the range of 17-19 mm, and a mass of about 1.0 g.

[0079] Terms 1.a. Glucono-δ-lactone (GDL); and b. Hypromellose (HPMC) 23. A pharmaceutical composition comprising: 2. The pharmaceutical composition comprises: a. Glucono-δ-lactone (GDL); b. gluconate; and c. Hypromellose (HPMC) 2. The pharmaceutical composition according to clause 1, comprising: 3. The pharmaceutical composition according to clause 2, wherein the gluconate salt is selected from the group consisting of sodium gluconate, potassium gluconate, calcium gluconate, magnesium gluconate, iron(II) gluconate, copper(II) gluconate, and zinc gluconate. 4. The pharmaceutical composition according to clause 2, wherein the gluconate is sodium gluconate (NaG). 5. The pharmaceutical composition comprises: a. Glucono-δ-lactone (GDL); b. Sodium gluconate (NaG); and c. Hypromellose (HPMC) 5. The pharmaceutical composition according to any one of clauses 2 and 4, comprising: 6. The pharmaceutical composition according to any one of clauses 1 to 5, wherein the pharmaceutical composition is a solid composition. 7. The pharmaceutical composition according to any one of clauses 1 to 6, wherein the pharmaceutical composition is for vaginal administration. 8. The pharmaceutical composition according to any one of clauses 1 to 7, wherein the GDL is released for at least 6 hours in vivo, such as at least 12 hours in vivo, such as at least 18 hours, such as at least 24 hours, such as at least 36 hours, such as at least 42 hours. 9. The pharmaceutical composition according to any one of clauses 1 to 8, wherein the GDL is released in vivo for at least 24 hours, such as at least 36 hours. 10. The pharmaceutical composition according to any one of clauses 1 to 9, wherein the GDL is released in vivo for a period of 72 hours or less, such as 48 hours or less. 11. The pharmaceutical composition according to any one of clauses 1 to 10, wherein the pharmaceutical composition is in the form of a pharmaceutical dosage form. 12. The pharmaceutical composition according to any one of clauses 1 to 11, wherein the pharmaceutical composition is a tablet. 13. The pharmaceutical composition according to clause 12, wherein the tablet has a mass of at least 0.5 g, such as at least 0.7 g, such as at least 0.85 g, such as at least 1.0 g, such as at least 1.25 g, such as at least 1.4 g. 14. The pharmaceutical composition according to any one of clauses 12-13, wherein the mass of the tablet is 2.0 g or less, such as 1.75 g or less, such as 1.5 g or less, such as 1.0 g or less, such as 0.9 g or less. 15. The pharmaceutical composition according to clause 12, wherein the mass of the tablet is in the range of 0.5 to 2.0 g, such as in the range of 0.7 to 1.75 g, such as in the range of 1.4 to 1.6 g, such as about 1.5 g. 16. The pharmaceutical composition according to clause 12, wherein the mass of the tablet is in the range of 0.5 to 2.0 g, such as in the range of 0.5 to 1.25 g, such as in the range of 0.7 to 1.0 g, such as about 0.85 g. 17. The pharmaceutical composition according to any one of clauses 12 to 16, wherein the tablet is bullet-shaped. 18. The pharmaceutical composition according to any one of clauses 12 to 17, wherein the tablet has a width of at least 5 mm, such as at least 7 mm, such as at least 9 mm, such as at least 10 mm. 19. The pharmaceutical composition according to any one of clauses 12 to 18, wherein the tablet has a width of 15mm or less, such as 12mm or less, such as 11mm or less, such as 10mm or less. 20. The pharmaceutical composition according to any one of clauses 12 to 17, wherein the tablet has a width in the range of 8 to 12 mm, such as in the range of 8.5 to 11 mm, such as 10 to 10.5 mm. 21. The pharmaceutical composition according to any one of clauses 12 to 17, wherein the tablet has a width in the range of 7.0 to 12 mm, such as in the range of 8.0 to 10 mm, such as in the range of 8.5 to 9.5 mm. 22. The pharmaceutical composition according to any one of clauses 12 to 21, wherein the tablet has a length of at least 10 mm, such as at least 15 mm, such as at least 20 mm. 23. The pharmaceutical composition according to any one of clauses 12 to 22, wherein the tablet has a length of 30 mm or less, such as 25 mm or less, such as 20 mm or less. 24. The pharmaceutical composition according to any one of clauses 12 to 21, wherein the tablet has a length in the range of 10 to 30 mm, such as in the range of 15 to 20 mm, such as in the range of 16 to 18 mm. 25. The pharmaceutical composition according to any one of clauses 12 to 21, wherein the tablet has a length in the range of 10 to 30 mm, such as in the range of 22 to 27 mm, such as in the range of 24 to 25 mm. 26. The pharmaceutical composition according to any one of clauses 1 to 25, wherein the amount of GDL is 50 to 500 mg, such as 100 to 400 mg, such as 250 to 350 mg, such as about 300 mg. 27. The pharmaceutical composition according to any one of clauses 1 to 26, wherein the composition comprises at least 5 wt% GDL, such as at least 10 wt%, such as at least 15 wt%, such as at least 20 wt% GDL. 28. The pharmaceutical composition according to any one of clauses 1 to 27, wherein the composition comprises no more than 50wt% GDL, such as no more than 40wt%, such as no more than 35wt%, such as no more than 30wt%, such as no more than 25wt%, such as no more than 20%wt% GDL. 29. The pharmaceutical composition according to any one of clauses 1 to 28, wherein the composition comprises GDL in the range of 10 to 30 wt%, such as 15 to 25 wt% GDL, such as about 20 wt% GDL. 30. The pharmaceutical composition according to any one of clauses 1 to 29, wherein the composition comprises gluconate in at least a concentration equivalent to an equimolar concentration of NaG, such as 10 wt% NaG, such as at least 15 wt% NaG, such as at least 20 wt% NaG. 31. The pharmaceutical composition according to any one of clauses 1-30, wherein the composition comprises at least 10 wt% NaG, such as at least 15 wt% NaG, such as at least 20 wt% NaG. 32. The pharmaceutical composition according to any one of clauses 1-31, wherein the composition contains no more than 30 wt% NaG, such as no more than 25 wt%, such as no more than 20 wt% NaG. 33. The pharmaceutical composition according to any one of clauses 1-32, wherein the composition comprises NaG in the range of 10-30 wt%, such as 15-25 wt%, such as 20-25 wt%, such as 24-25 wt% NaG. 34. A pharmaceutical composition according to any one of clauses 1 to 33, wherein the molar ratio of GDL to gluconate is 2:1 to 1:2, such as 3:2 to 2:3, such as about 1:1. 35. A pharmaceutical composition according to any one of clauses 1 to 34, wherein the molar ratio of GDL to NaG is 2:1 to 1:2, such as 3:2 to 2:3, such as about 1:1. 36. The pharmaceutical composition according to any one of clauses 1 to 35, wherein the HPMC is selected from the group consisting of HPMC substituted types 2208, 2910, 1828 and 2906. 37. The pharmaceutical composition according to any one of clauses 1 to 36, wherein the HPMC is of substituted type 2208 or 2910. 38. The pharmaceutical composition according to any one of clauses 1 to 37, wherein the HPMC has a viscosity of at least 10 mPas, such as at least 15 mPas, such as at least 20 mPas, such as at least 25 mPas, such as at least 30 mPas, such as at least 35 mPas, such as at least 40 mPas, such as at least 45 mPas, such as at least 50 mPas, such as at least 55 mPas, such as at least 60 mPas, such as at least 65 mPas, such as at least 70 mPas, such as at least 75 mPas. 39. A pharmaceutical composition according to any one of clauses 1 to 38, wherein the HPMC has a viscosity of 400.000mPas or less, such as 300.000mPas or less, such as 200.000mPas or less, such as 150.000mPas or less, such as 100.000mPas or less, such as 50.000mPas or less, such as 10.000mPas or less, such as 1.000mPas or less, such as 500mPas or less, such as 250mPas or less. 40. The pharmaceutical composition according to any one of clauses 1 to 39, wherein the HPMC has a viscosity in the range of 50 to 200 mPas, such as about 100 mPas. 41. A pharmaceutical composition according to any one of clauses 1 to 40, wherein the HPMC has a viscosity in the range of 50.000 mPas to 200.000 mPas, such as about 100.000 mPas. 42. The pharmaceutical composition according to any one of clauses 1 to 41, wherein the composition comprises at least 5 wt% HPMC, such as at least 10 wt%, such as at least 10 wt%, such as at least 15 wt%, such as at least 20 wt%, such as at least 25 wt%, such as at least 30 wt%, such as at least 35 wt%, such as at least 40 wt%, such as at least 45 wt%, such as at least 50 wt% HPMC. 43. The pharmaceutical composition according to any one of clauses 1 to 42, wherein the composition comprises 60wt% or less HPMC, such as 55wt% or less, such as 50wt% or less, such as 45wt% or less, such as 45wt% or less, such as 40wt% or less, such as 35wt% or less, such as 30wt% or less, such as 25wt% or less, such as 20wt% or less, such as 15wt% or less, such as 10wt% or less HPMC. 44. The pharmaceutical composition according to any one of clauses 1 to 43, wherein the composition comprises HPMC in the range of 5 to 60 wt%, such as 15 to 40 wt%, such as 20 to 35 wt% HPMC. 45. The pharmaceutical composition according to any one of clauses 1 to 44, wherein the composition further comprises silica. 46. ​​The pharmaceutical composition according to clause 45, wherein the silica is selected from the group consisting of colloidal anhydrous silica, colloidal silicone dioxide, colloidal hydrated silica and hydrophobic colloidal silica. 47. A pharmaceutical composition according to any one of clauses 45-46, wherein the composition comprises 0.1-5 wt% silica, such as in the range 0.1-2 wt%, such as about 0.5 wt% silica. 48. The pharmaceutical composition of any one of clauses 1 to 47, wherein the composition further comprises a lubricant. 49. The pharmaceutical composition according to clause 48, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, sucrose palmitate and sucrose stearate. 50. The pharmaceutical composition according to any one of clauses 48-49, wherein the lubricant is magnesium stearate. 51. A pharmaceutical composition according to any one of clauses 48 to 50, wherein the composition comprises 0.1 to 5 wt% of lubricant, such as 0.1 to 2 wt%, such as 0.70 to 1.3 wt%, such as about 1 wt% of lubricant. 52. The pharmaceutical composition according to any one of clauses 1 to 51, wherein the composition further comprises starch. 53. The pharmaceutical composition according to clause 52, wherein the starch is pregelatinized starch. 54. The pharmaceutical composition according to any one of clauses 1 to 53, wherein the composition comprises at least 10 wt% starch, such as at least 15 wt%, such as at least 20 wt%, such as at least 30 wt%, such as at least 40 wt%. 55. The pharmaceutical composition according to any one of clauses 1 to 54, wherein the composition comprises no more than 45 wt% starch, such as no more than 40 wt%, such as no more than 35 wt%, such as no more than 30 wt%, such as no more than 25 wt%, such as no more than 20 wt%. 56. A pharmaceutical composition according to any one of clauses 1 to 55, wherein the composition comprises 10 to 50 wt% starch, such as 10 to 30 wt%, such as 15 to 25 wt%, such as 10 to 20 wt% starch. 57. The pharmaceutical composition of any one of clauses 1 to 56, wherein the composition further comprises cellulose. 58. The pharmaceutical composition according to clause 57, wherein the cellulose is selected from the group consisting of microcrystalline cellulose (MCC), siliconized microcrystalline cellulose and powdered cellulose. 59. A pharmaceutical composition according to any one of clauses 57 to 58, wherein the cellulose is MCC. 60. The pharmaceutical composition according to clause 59, wherein the MCC has a nominal particle size of at least 20 μm, such as at least 50 μm, such as at least 75 μm, such as at least 100 μm, such as at least 125 μm, such as at least 140 μm, such as at least 150 μm, such as at least 160 μm. 61. A pharmaceutical composition according to any one of clauses 59 to 60, wherein the MCC has a nominal particle size of 200 μm or less, such as 190 μm or less, such as 180 μm or less, such as 170 μm or less, such as 160 μm or less. 62. A pharmaceutical composition according to any one of clauses 59 to 61, wherein the MCC has a nominal particle size in the range of 140 to 200 μm, such as about 150 to about 180 μm. 63. A pharmaceutical composition according to any one of clauses 57 to 62, wherein the composition comprises at least 20 wt% cellulose, such as at least 30 wt%, such as at least 40 wt%, such as at least 50 wt% cellulose. 64. A pharmaceutical composition according to any one of clauses 57 to 63, wherein the composition comprises no more than 60 wt% cellulose, such as no more than 50 wt%, such as no more than 40 wt%, such as no more than 30 wt% cellulose. 65. A pharmaceutical composition according to any one of clauses 57 to 62, wherein the composition comprises 20 to 60 wt% cellulose, such as 20 to 30 wt%, such as 30 to 40 wt% or such as 50 to 60 wt% cellulose. 66. The pharmaceutical composition of any one of clauses 1-65, wherein the composition further comprises lactose or a sugar alcohol. 67. The pharmaceutical composition according to clause 66, wherein the lactose is α-lactose. 68. A pharmaceutical composition according to any one of clauses 66 to 67, wherein the lactose is in the form of a monohydrate. 69. The pharmaceutical composition according to clause 66, wherein the sugar alcohol is mannitol. 70. A pharmaceutical composition according to any one of clauses 66 to 69, wherein the composition comprises lactose or sugar alcohol in the range of 40 to 70 wt%, such as 50 to 60 wt% lactose or sugar alcohol. 71. A pharmaceutical composition according to any one of clauses 1 to 70, wherein the composition comprises or consists of GDL, gluconate, HPMC, starch, silica and magnesium stearate. 72. A pharmaceutical composition according to any one of clauses 1 to 71, wherein the composition comprises or consists of 10 to 25 wt% GDL; 15 to 30 wt% NaG; 30 to 40 wt% HPMC; 15 to 45 wt% starch; 0.25 to 1.25 wt% silica; and 0.5 to 1.5 wt% magnesium stearate. 73. A pharmaceutical composition according to any one of clauses 1 to 72, wherein the composition comprises or consists of 15 to 25 wt% GDL; 20 to 30 wt% NaG; 30 to 40 wt% HPMC; 15 to 25 wt% starch; 0.25 to 1.25 wt% silica; and 0.5 to 1.5 wt% magnesium stearate. 74. The pharmaceutical composition of any one of clauses 1-73, wherein the composition comprises or consists essentially of approximately 20 wt% GDL; 24.5 wt% NaG; 35 wt% HPMC; 19 wt% starch; 0.5 wt% silica; and 1 wt% magnesium stearate. 75. The pharmaceutical composition according to clause 74, wherein the HPMC has a viscosity of 100.000 mPas. 76. The pharmaceutical composition according to any one of clauses 74 to 75, wherein the HPMC has a degree of substitution of 2208. 77. The pharmaceutical composition of any one of clauses 1-76, wherein the composition comprises or consists essentially of approximately 20 wt% GDL; 24.1 wt% NaG; 30 wt% HPMC; 24.4 wt% starch; 0.5 wt% silica; and 1 wt% magnesium stearate. 78. The pharmaceutical composition of any one of clauses 1-77, wherein the composition comprises or consists essentially of approximately 20 wt% GDL; 24.1 wt% NaG; 35 wt% HPMC; 19.4 wt% starch; 0.5 wt% silica; and 1 wt% magnesium stearate. 79. The pharmaceutical composition of any one of clauses 1-78, wherein the composition comprises or consists essentially of approximately 20 wt% GDL; 24.5 wt% NaG; 35 wt% HPMC; 19 wt% starch; 0.5 wt% silica; and 1 wt% magnesium stearate. 80. The pharmaceutical composition of any one of clauses 1-79, wherein the composition comprises or consists essentially of approximately 20 wt% GDL; 24.5 wt% NaG; 35 wt% HPMC; 19.25 wt% starch; 0.5 wt% silica; and 0.75 wt% magnesium stearate. 81. The pharmaceutical composition of any one of clauses 1-80, wherein the composition comprises or consists essentially of about 20 wt% GDL; 24.5 wt% NaG; 35 wt% HPMC; 18.75 wt% starch; 0.5 wt% silica; and 1.25 wt% magnesium stearate. 82. The pharmaceutical composition of any one of clauses 1, wherein the composition comprises or consists essentially of approximately 20 wt% GDL; 24.5 wt% NaG; 35 wt% HPMC; 19 wt% starch; 0.5 wt% silica; and 1 wt% magnesium stearate. 83. The pharmaceutical composition of any one of clauses 1-82, wherein the composition comprises or consists essentially of about 10 wt% GDL; 12.25 wt% NaG; 35 wt% HPMC; 41.5 wt% starch; 0.5 wt% silica; and 1.25 wt% magnesium stearate. 84. The pharmaceutical composition of any one of clauses 1-83, wherein the composition comprises or consists essentially of approximately 10 wt% GDL; 12.25 wt% NaG; 35 wt% HPMC; 41.5 wt% starch; 0.5 wt% silica; and 0.75 wt% magnesium stearate. 85. The pharmaceutical composition of any one of clauses 1-84, wherein the composition comprises or consists essentially of approximately 15 wt% GDL; 18.375 wt% NaG; 35 wt% HPMC; 30.125 wt% starch; 0.5 wt% silica; and 1 wt% magnesium stearate. 86. The pharmaceutical composition of any one of clauses 1-85, wherein the composition comprises or consists essentially of 15-25 wt% GDL; 20-30 wt% NaG; 45-65 wt% HPMC; 0.25-1.25 wt% silica; and 0.5-1.5 wt% magnesium stearate. 87. The pharmaceutical composition of any one of clauses 1-86, wherein the composition comprises or consists essentially of approximately 20 wt% GDL; 24.1 wt% NaG; 54.4 wt% HPMC; 0.5 wt% silica; and 1 wt% magnesium stearate. 88. A pharmaceutical composition according to any one of clauses 1 to 87, wherein the composition comprises or consists of 15 to 25 wt% GDL; 20 to 30 wt% NaG; 25 to 40 wt% HPMC; 10 to 30 wt% MCC; 0.25 to 1.25 wt% silica; and 0.5 to 1.5 wt% magnesium stearate. 89. The pharmaceutical composition of any one of clauses 1-88, wherein the composition comprises or consists essentially of approximately 20 wt% GDL; 24.1 wt% NaG; 30 wt% HPMC; 24.4 wt% MCC; 0.5 wt% silica; and 1 wt% magnesium stearate. 90. A pharmaceutical composition according to any one of clauses 1 to 89, provided that the sum of the components does not exceed 100 wt%. 91. The pharmaceutical composition according to any one of clauses 1 to 90, wherein the pharmaceutical composition is stable at 25°C for at least 6 months, or at least 6 months at 40°C. 92. A pharmaceutical composition according to any one of clauses 1 to 91, wherein the composition does not contain an additional antifungal agent. 93. The pharmaceutical composition according to clause 92, wherein the antifungal agent is selected from the group consisting of miconazole, terconazole, isoconazole, fenticonazole, fluconazole, nystatin, ketoconazole, clotrimazole, butoconazole, econazole, tioconazole, itraconazole, 5-fluoracil, and metronidazole. 94. A pharmaceutical composition according to any one of clauses 1 to 93 for use as a medicament. 95. A pharmaceutical composition according to any one of clauses 1 to 94 for use in the treatment of a microbial infection. 96. The pharmaceutical composition for use according to clause 95, wherein the microbial infection is a urogenital infection. 97. A pharmaceutical composition for use according to any one of clauses 95-96, wherein the microbial infection is a vaginal infection. 98. A pharmaceutical composition for use according to any one of clauses 95 to 97, wherein the microbial infection is selected from the group consisting of a fungal infection, a bacterial infection and a mixed fungal and bacterial infection. 99. A pharmaceutical composition for use according to any one of clauses 95 to 98, wherein the fungal infection is a mycosis. 100. The pharmaceutical composition for use according to clause 99, wherein the fungal disease is candidiasis. 101. A pharmaceutical composition for use according to clause 100, wherein the candidiasis is vulvar and vaginal candidiasis or urogenital candidiasis. 102. The pharmaceutical composition for use according to clause 98, wherein the bacterial infection is bacterial vaginosis. 103. A pharmaceutical composition for use according to clause 98, wherein the fungal infection is caused by a pathogen selected from the group consisting of Candida albicans, Candida krusei, Candida glabrata, Candida tropicalis, Trichophyton verrucosum, Trichophyton rubrum, Trichophyton violaceum, Trichophyton tonsurans, Microsporum canis, Malassezia and / or Aspergillus. 104. Bacterial infections include those caused by Gardnerella vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Treponema pallidum (syphilis), Atopobium vaginae, Prevotella spp., Mobiluncus spp., Peptostreptococcus spp., Porphyromonas spp., Mycoplasma hominis, Bacteroides spp., Ureaplasma urealyticum, Streptococcus, Enterobacteriaceae, Enterococcus, Staphylococcus aureus, Propionibacterium, Escherichia coli, Klebsiella, Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, baumanii, Streptococcus pyogenes, Streptococcus agalactiae, β-hemolytic streptococci groups C and G and / or Porphyromonas gingivalis. 105. The pharmaceutical composition for use according to any one of clauses 95 to 103, wherein the infectious disease is an infectious disease in a mammal. 106. A pharmaceutical composition for use according to any one of clauses 95 to 104, wherein the mammal is a human. 107. The pharmaceutical composition for use according to any one of clauses 95 to 106, wherein the mammal is a female. 108. A pharmaceutical composition for use according to any one of clauses 95 to 107, wherein the female is pregnant. 109.a.Sieving GDL, gluconate, and HPMC; mixing the sieved ingredients of ba; and The process of compressing the powder mixture of cb into tablets. 89. A method for producing a pharmaceutical composition according to any one of clauses 1 to 88, comprising: 110. a. sieving GDL, gluconate, and HPMC; mixing the sieved components of ba with the sieved silica; mixing a portion of the cb mixture with a lubricant; adding and mixing the mixture of (d) and (c) to the remaining mixture of (b); and e. Compressing the powder mixture of 109.b. into tablets. 110. The method of claim 109, comprising: 111. The method of any one of clauses 109-110, wherein the breaking force for the formed tablet is at least 10 kp. 112. The method according to any one of clauses 109 to 111, wherein the tablet is bullet-shaped with a width in the range of 8 to 12 mm, such as in the range of 9 to 11 mm, such as in the range of 10 to 10.5 mm, and a length in the range of 15 to 30 mm, such as in the range of 17 to 19 mm or such as in the range of 20 to 30 mm, such as in the range of 22 to 27 mm, such as in the range of 24 to 25 mm. 113. The method of any one of clauses 109-112, wherein the tablet forming step is carried out by compression with a 10.3 x 24.45 mm punch / die set. 114. A method for the treatment of a microbial infection, comprising administering to a subject in need thereof a pharmaceutical composition according to any one of clauses 1 to 88. 115. Use of a pharmaceutical composition according to any one of clauses 1 to 88 in the manufacture of a medicament for the treatment of a microbial infection.

[0080] Working Example Example 1: Formulations based on design limit points The composition of the formulation is provided in Table 1. The composition is given simply as a percentage since the tablet weight obtained was unknown. The target tablet weight was approximately 0.85 g, ensuring that the tablet weight was similar for all batches.

[0081] Table 1. Formulations based on design limit points. Batch sizes ranged from 20 to 100 g. [Table 1] TIFF0007610847000002.tif210162

[0082] The blending was carried out in a Turbula T2F (tumbling mixer) in a glass container of suitable volume. First, GDL, NaG, HPMC, lacto and MCC were sieved through a 1.00 mm screen before blending. Silica was then pre-blended with a similar amount of HPMC by shaking in a plastic bag and sieving through a 1.00 mm screen and added to the other powders except MgSt in the blender container. Blending was carried out for 8 minutes at 32 rpm. Lubricant (MgSt) was pre-blended with a similar amount of 8-minute powder blend, sieved through 1.00 mm, added to the remainder of the 8-minute powder blend and blended for 2 minutes at 22 rpm. Formulation D was the exception and was blended in a mortar with a pestle.

[0083] The powder mixtures were compressed into tablets in a rotary tablet press (Fette 52i) with 9 × 17 mm punch / die at the same loading. Due to the different densities of the formulations, tablets weighing 0.75–0.97 g were obtained with compression forces of 2–13 kN (corresponding to approximately 100–110 MPa).

[0084] The dissolution data are summarized in Table 2. Dissolution tests were performed in a paddle apparatus (Apparatus 2, Ph.Eur.) at 37° C. in 500 mL of 50 mM acetate buffer (pH 4.0) at 50 rpm. GDL and NaG contents were determined by HPLC and expressed as GDL. Normalization was performed: 100% dissolution was assumed after 24 or 48 hours (when the level was reached) and the calculation of the percentage dissolved at the previous time point was performed based on the actual 24 or 48 hour values.

[0085] Table 2. Normalized dissolution data, 48 hours [Table 2]

[0086] Dissolution studies showed that the dissolution from formulations D and F, which used 20% GDL and 20% HPMC with low viscosity, was more rapid compared to formulations G and H, which used 20% GDL and 24.1% NaG, 30% HPMC K4M or K200M, and MCC as filler. It can be observed that formulation D contained a water-soluble filler (Lact) and formulation F contained a water-insoluble filler. Formulations G and H, which have significantly different viscosities of HPMC, gave similar dissolution profiles.

[0087] Since the high viscosity of HPMC generally reduces the dissolution rate of solid oral dosage forms, a highly viscous HPMC type was selected for further formulation studies with an in vivo release time of approximately 48 hours. Formulation H was the prototype for Example 2.

[0088] Example 2: Formulations based on different proportions of HPMC and starch The batch size for the formulations in Table 3 was 500 g based on Formulation H.

[0089] Table 3. Complete composition of three formulations based on different proportions of hypromellose and starch, in g or % (in brackets) [Table 3] TIFF0007610847000005.tif148162

[0090] The blending was carried out in a Turbula T2F2L glass vessel. First, the GDL, NaG, HPMC and starch were sieved through a 1.00 mm screen before blending. The silica was then pre-blended with a similar amount of HPMC by shaking in a plastic bag and sieving through a 1.00 mm screen and added to the other four powders in the mixer vessel. Blending was carried out for 8 minutes at 32 rpm. The lubricant (MgSt) was pre-blended with a similar amount of the 8 min powder blend, sieved through 1.00 mm, added to the remainder of the 8 min powder blend and blended for 2 minutes at 22 rpm. The powder blend was compressed into tablets on a Fette 52i with two sets of punch / dies 9×17 mm. The tablet weights of the batches were similar at about 0.85 g.

[0091] The technical properties of the tablets are displayed in Table 4. The friability was tested according to the European Pharmacopoeia 2.9.7. Friability of uncoated tablets. The average weight was affected by the bulk density of the formulation, but the technical properties for tablets compressed at practical compression forces were acceptable.

[0092] Table 4. Technical properties of tablets at actual compression forces [Table 4]

[0093] The dissolution data is summarized in Table 5. Dissolution testing was performed as in Example 1.

[0094] Table 5. Normalized dissolution data, 24 hours [Table 5]

[0095] Formulation I, based on formulation H (Table 3), replaced MCC with starch but showed a slight decrease in dissolution rate compared to formulation K (no starch) (Table 5). Formulation K showed poorer flow than the other two formulations.

[0096] Example 3: Formulations based on the effect of low viscosity HPMC The effect of low viscosity HPMC in the formulation was studied in two formulations: The batch size was 600 g of powder mix.

[0097] Table 6. Formulations in g and percentages (in brackets) [Table 6] TIFF0007610847000009.tif67162

[0098] The blending was carried out in a Turbula T2F2L glass vessel. First, the GDL, NaG, HPMC and starch were sieved through a 1.00 mm screen before blending. Then, the silica was pre-blended with a similar amount of HPMC by shaking in a plastic bag and sieving through a 1.00 mm screen, and added to the other four powders in the mixer vessel. Blending was carried out at 32 rpm for 8 minutes.

[0099] A lubricant (MgSt) was premixed with a similar amount of the 8 minute powder mix, sieved through 1.00 mm, added to the remainder of the 8 minute powder mix and mixed for 2 minutes at 22 rpm.

[0100] The powder mixture was compressed into tablets on a Fette 52i with two sets of punch / dies 9x17mm. Tablet weights were kept similar at approximately 0.85g for both batches. The main compression force setting was 18kN.

[0101] The dissolution test was carried out as in Example 1. The technical properties were determined as described in Example 2.

[0102] Table 7. Normalized dissolution data [Table 7] Table 8. Technical characteristics [Table 8]

[0103] Formulation L (HPMC type with a viscosity of 15 mPas) had to be compressed at very high pressure (32 kN) to obtain tablets with acceptable technical properties (breaking force and friability), but the dissolution was rapid (Table 7). Formulation M (HPMC type with a viscosity of 100 mPas) dissolves slower than formulation L, but faster than formulation J with a HPMC type of 200 000 mPas. The technical properties (breaking force and friability) of formulation M were acceptable (Table 8). Therefore, if a low viscosity type of HPMC is included in the formulation, type K100 is selected.

[0104] Example 4: Formulation based on the effect of concentration of drug substance The effect of drug substance concentration (i.e. sum of GDL and NaG), ratio of low to high viscosity HPMC, pregelatinized starch concentration, and lubricant concentration on the vaginal tablets was studied in a fractional factorial design. The formulations used are listed in Table 9. Hypromellose of type K100 (100 mPas) and K100M (100 000 mPas) were employed. High viscosity HPMC K200M (200 000 mPas) was replaced by K100M. The batch size was 500 g.

[0105] Table 9. Composition of formulations N to T (%) [Table 9]

[0106] The mixing was carried out in a similar manner as in Example 3. Tablets were compressed in a rotary press with 9×17 mm oval punches at a pressure of 18 kN (corresponding to approximately 150 MPa) with an intended weight of approximately 0.8 g.

[0107] Tablets with acceptable technical properties - breaking force 8.2-12.2 kp, crushability 0.28-0.44%, uniformity of dosage units expressed as RSD 0.8-1.8% - were obtained for all formulations.

[0108] The same dissolution test procedure as in Example 1 was used, but the contents of GDL and NaG were determined by UPLC and expressed as GDL.

[0109] Dissolution results were similar, except that formulation N, which had a lower level of drug substance, a higher level of high viscosity HPMC, a higher level of starch and a higher level of lubricant, was somewhat slower as expected (Table 10).

[0110] Table 10. Normalized lysis results, 2–24 hours [Table 10]

[0111] Considering the dissolution profile and technical properties, formulation P was selected for refinement. A slight modification of formulation P in lubricant and starch concentration was selected as formulation C (Table 11).

[0112] Example 5: Effect of Compressive Force on Dissolution Rate Formulation C was produced in a batch size of 700 g. The mix was otherwise similar to the planned batch. Tablet compression was performed at 18-24 kN.

[0113] Table 11. Composition, % [Table 11] TIFF0007610847000015.tif76162

[0114] The technical properties of the tablets are mainly affected by the compression force, which is fixed at 18 kN in a fractional factorial design. The effect of compression force was tested separately for formulations P and C.

[0115] The effect of compression force on the dissolution rate was examined for Formulations C and P. The dissolution test was carried out in the same manner as described in Example 1.

[0116] Table 12. Normalized dissolution data, 2–24 hours [Table 12]

[0117] The data from Table 12 show that dissolution was similar for tablets of Formulations C and P compressed at 18-19 kN and for tablets of Formulation C compressed at 24 kN. The technical properties of the tablets were acceptable. Therefore, dissolution was not affected by normal compression forces giving acceptable technical tablet properties.

[0118] Example 6: 10.3 x 24.5 mm punch on a single punch tablet machine Tablets with a weight of about 1.5 g were desired, which required a die / punch set with dimensions that were not available on the available rotary tablet press. A 10.3×24.5 mm punch / die set was procured for a single punch tablet machine. This equipment was used to produce tablets for clinical trials and stability studies. At the same time, the batch size was increased to 1.8 kg (Formulation A). A batch of powder mix of size 700 g for Formulation A was produced with a 10.3×24.5 mm tool prior to Formulation A. The dissolution data in Table 13 shows that the dissolution profile of the 10.3×24.5 mm bullet-shaped tablets was similar to the 9×17 mm oval tablets.

[0119] Table 13. Normalized dissolution data [Table 13]

[0120] Example 7: Formulations for biocompatibility and stability studies The batch size for Formulation A was 1800 g of powder mix. The batch formulation and composition are summarized in Table 14.

[0121] Table 14. Formulation A batch mix and composition (biocompatibility and stability studies) [Table 14] TIFF0007610847000019.tif83162

[0122] Mixing was done in a Turbula T10B (tumbling mixer), stainless steel 6 L vessel. GDL, NaG, HPMC and starch were sieved through a 1.00 mm screen. Silica was premixed with a similar amount of HPMC by shaking in a plastic bag and sieving through a 1.00 mm screen and added to the other four powders in the mixer vessel. Mixing was done for 8 minutes at 32 rpm. MgSt was premixed with a similar amount of the 8 min powder mix, sieved through 1.00 mm, added to the remainder of the 8 min powder mix and mixed for 2 minutes at 23 rpm.

[0123] The powder mixture was compressed into bullet-shaped 10.3 x 24.5 mm tablets in a Korsch EK-0 single punch tablet press. Tablets weighing 1.5 g were obtained with acceptable friability (0.3%) and breaking force (17-18 kp).

[0124] Dissolution testing was performed similarly to Example 2. The dissolution results are presented in Table 15.

[0125] Table 15. Normalized lysis data, percent lysis [Table 15]

[0126] This example demonstrates the preparation of tablets containing GDL, NaG and HPMC that are stable and biocompatible.

[0127] Example 8: Formulations based on different fillers The effect of HPMC viscosity and type of filler was investigated in a fractional factorial design. The formulations used are listed in Table 16.

[0128] Table 16. Composition in percentage (%) [Table 16]

[0129] The technical characteristics of the tablets are displayed in Table 17. The friability was tested according to European Pharmacopoeia 2.9.7. Friability of uncoated tablets.

[0130] Table 17. Technical characteristics [Table 17] TIFF0007610847000023.tif27162

[0131] Formulations U-Y resulted in tablets with suitable technical properties.

[0132] The dissolution data is summarized in Table 18. The dissolution test was carried out in the same manner as in Example 1.

[0133] Table 18. Normalized dissolution data, 24 hours [Table 18]

[0134] Formulations containing mannitol were less adhesive than the corresponding compositions containing MCC. Furthermore, MCC was found to have better binding properties than mannitol.

[0135] The compositions containing HPMC 100 mPas dissolved more quickly than the corresponding compositions containing HPMC 4000 mPas.

[0136] Of the formulations tested in Example 8, formulations U and V are most suitable for once-daily administration.

[0137] Example 9: Formulations based on formulations U and V The effect of HMPC, MCC and lubricant concentrations was investigated and the formulations used are listed in Table 19.

[0138] Table 19. Composition in percentage (%) [Table 19] TIFF0007610847000026.tif100162

[0139] The technical characteristics of the tablets are displayed in Table 20. The friability was tested according to European Pharmacopoeia 2.9.7. Friability of uncoated tablets.

[0140] Table 20. Technical characteristics [Table 20]

[0141] Formulations U-Y resulted in tablets with suitable technical properties.

[0142] The dissolution data is summarized in Table 21. The dissolution test was carried out in the same manner as in Example 1.

[0143] Table 21. Normalized dissolution data, 24 hours [Table 21] TIFF0007610847000029.tif28162

[0144] Example 10: Fluid model for the dissolution of vaginal tablets of Formulation A The vaginal fluid model (Figure 1) consists of a reservoir with distilled water (approximately 1 L), a peristaltic pump, a glass column (internal diameter 30 mm, height 130 mm) and a fraction collector. Water is pumped into the glass column at a rate of 0.1 mL per minute under normal pressure. The estimated volume of cervical secretions is 0.51 mL [Mitchell, C.; Paul, K.; Agnew, K.; Gaussman, R.; Coombs, RW; Hitti, J. Journal of clinical microbiology 2011, 49, 735]. To simulate the vaginal mucosa, the vaginal tablet is wrapped in an artificial sponge (Wettex® made from regenerated cellulose, height 50 mm). The glass column is heated with an infrared heater (220 V, 60 W) at a distance of 60 mm to obtain a core temperature of 35 °C. The fluid is collected using a fraction collector set at 60 min per fraction. Vaginal tablets of formulations A, U, X, V, Z1 and Z5 were tested in independent experiments (Figure 2). The pH of each fraction was measured by a pH electrode. The results show that the active substance is released to give an efficient dose, as indicated by a drop in pH.

[0145] Example 11: Stability Study Tablets of Formulation A were packaged in blister materials consisting of Teknilid® 1250 and Tekniflex® VPOA 10300 (PVC / EVOH / ACLAR) as foil with lid (aluminum). Stability of Formulation A in the blisters was evaluated in technical stability studies at conditions of 25° C. / 60% RH and 40° C. / 75% RH. Stability of the formulations was observed for 1, 3, 6 and 12 months. See Tables 22 and 23. Three batches of Formulation A tablets were also produced under GMP conditions and stability was confirmed for all three batches for at least 12 months (data not shown).

[0146] Table 22. Assay (% of expected content) [Table 22]

[0147] Table 23. Weight gain (% of initial weight) [Table 23]

[0148] For all analyses, formulation A was found to be within the acceptable range, i.e., 90-110%.

[0149] Example 12: Cytotoxicity test of formulation A Glucono-delta-lactone is a normal intermediate in glucose metabolism via the pentose phosphate cycle in mammals. Several studies on humans have been conducted using oral doses of 3 g to 50 g of GDL with no signs of toxicity. The studies reviewed showed no evidence of carcinogenic, teratogenic, or genotoxic potential of GDL, or D-gluconic acid or its magnesium, potassium, calcium, or sodium salts. In addition, both the U.S. Food and Drug Administration (FDA) and the International Programme on Chemical Safety (ICPS) of the World Health Organization (WHO) have approved GDL as a safe food additive. [International Programme on Chemical Safety (ICPS)] Glucono-Delta-Lactone and the Calcium, Magnesium, Potassium, and Sodium Salts of Gluconic Acid 1999; available at http: / / www.inchem.org / documents / jecfa / jecmono / v042je12.htm; U.S. Food and Drug Administration, 21 CFR 184.1318].

[0150] Cytotoxicity Test The cytotoxic effect of formulation A was analyzed by incubating the test article in indirect contact with agarose-overlaid L929 cells for at least 24 hours and staining with neutral red. The decolorization index and lysis index were determined microscopically according to the size of the decolorized area and the number of lysed cells around and under the test article, respectively. The cellular response was recorded as decolorization index / lysis index and graded on a scale of 0 to 3.

[0151] Before testing, the test articles were finely ground. High density polyethylene material and 0.1% zinc-diethyldithiocarbamate (ZDEC) polyurethane film were used as negative and positive controls, respectively. Each tissue culture dish was treated with two samples of the test article, one negative control and one positive control. Three culture dishes were treated in parallel. After the incubation period, the cells around and under the samples were analyzed with an inverted microscope.

[0152] result The results of the cytotoxicity tests are shown in the table below.

[0153] Table 24. Decolorization index [Table 24]

[0154] Table 25. Dissolution index [Table 25]

[0155] Table 26. Interpretation of Cytotoxicity [Table 26]

[0156] conclusion The test article (Formulation A) was classified as mildly to moderately cytotoxic. Controls confirmed the validity of the study.

[0157] Example 13: Sensitization test The local lymph node assay (LLNA) is a method for identifying skin sensitizing test articles that measures the proliferation of lymphocytes isolated from lymph nodes draining the site of exposure (dorsal of the ear) in mice. Lymphocyte proliferation is 3The incorporation of H-methylthymidine is measured by determining it. Formulation A was extracted with two different media: saline 0.9% NaCl (polar extraction media) and acetone / olive oil 4:1 (v / v) (non-polar extraction media) according to ISO 10993-12 [ISO 10993-12:2012 "Biological evaluation of medical devices-Part 12: Sample preparation and reference materials"].

[0158] Topical application of the extract was performed once a day for three consecutive days, with five mice per test group. Five days after the first topical treatment, all mice showed 3 H-methylthymidine was administered intravenously and the mice were sacrificed 5 hours later. Lymph node cells from the draining "auricular lymph nodes" were pooled from each animal (2 lymph nodes per animal). 3 H-methylthymidine incorporation was measured and compared with that recorded for control animals (stimulation index) in disintegrations per minute per lymph node (DPM / node) and lymph node cells in test animals. 3 The results were expressed as the percentage of H-methylthymidine incorporation. Background values ​​were subtracted. The stimulation index of the test article extracts on lymph node cells of test animals was compared to that recorded for lymph nodes of control animals (stimulation index of 3.0 or greater). 3 A substance is considered a "sensitizer" to the LLNA if it produces a 3-fold or greater increase in 3H-methylthymidine incorporation.

[0159] result The polar test article extracts were compared to those recorded for control animals (stimulation index) to determine the effect of the test article on lymph node cells. 3 The ratio of H-methylthymidine incorporation was 1.2 for the non-polar test article extract in lymph node cells of test animals compared to that recorded for control animals (stimulation index). 3The ratio of H-methylthymidine incorporation was 1.3. All animals showed expected weight gain throughout the study, including a maximum weight loss of 2 g. All animals survived the study period without showing clinical signs. Both polar and non-polar positive control substances exceeded a stimulation index of 3 confirming the reliability of the test system.

[0160] conclusion Under the conditions of this study, Formulation A did not elicit responses that could be identified as sensitizing since the irritation index of both polar and non-polar test article extracts was below a irritation index of 3.

[0161] Example 14: Irritation Test The potential of Formulation A to cause irritation to vaginal tissue was investigated in albino rabbits. Formulation A was extracted with saline 0.9% NaCl according to ISO 10993-12 [ISO 10993-12:2012 "Biological evaluation of medical devices - Part 12: Sample preparation and reference materials"]. The supernatant of the test article extract was applied to the animals. Extraction medium was used as a control for three animals. The test article extract was applied to three animals using a flexible plastic blunt-tipped cannula with a syringe introduced directly into the vagina. The procedure was repeated at intervals of 24 ± 2 hours for five consecutive days.

[0162] Clinical Observations 24±2 hours after the first application and immediately prior to each treatment, the appearance of the vaginal opening and perineum were observed and recorded for signs of discharge (grades 0-3), erythema (grades 0-4) and edema (grades 0-4). Additionally, animals were observed for clinical signs of toxicity.

[0163] Visual evaluation 24±2 hours after the last application, the entire vagina was dissected, opened longitudinally, and macroscopically examined for signs of irritation, injury to the epithelial layer of tissue and necrosis. Erythema and edema were recorded according to a scoring system ranging from 0 to 4. All parts of the vagina and surrounding tissue were then fixed in 4% neutral buffered formaldehyde for further histopathological examination.

[0164] Histopathological evaluation The effects of irritation on the tissues were graded according to a 0-4 grading system for epithelium, leukocyte infiltration, vascular obstruction and edema.

[0165] The microscopic grades for all animals in a test group were added and the sum divided by the number of observations to obtain the test group mean. The same procedure was performed for the control group. The control group mean was subtracted from the test group mean to obtain the stimulation index (Table 25).

[0166] Table 27. Irritation index [Table 27]

[0167] result Clinical Observations 24 hours after the first application and before each treatment, the appearance of the vaginal opening and perineum was observed and recorded for signs of discharge, erythema and edema. None of the animals showed excessive discharge, erythema, eschar and / or edema. No signs of irritation were found. No signs of toxicity were recorded.

[0168] Visual inspection Gross examination of the intravaginal area revealed no signs of irritation or necrosis.

[0169] Histopathological evaluation There were no signs of a notable irritation response in the vaginal or peri-vaginal tissues following daily intravaginal application of Formulation A (test article) or the extraction vehicle (control article) to New Zealand White rabbits for 5 consecutive days. This finding was unrelated to treatment and did not represent a physiological background change.

[0170] Table 28. Individual and average scores for microscopic findings [Table 28] TIFF0007610847000037.tif95162

[0171] conclusion Under the conditions of this experiment, the irritation index was 0.33. In vivo irritation showed that no signs of irritation or necrosis were observed in the macroscopic evaluation. Also, the histopathological evaluation gave no indication of irritation of the vaginal mucosa. Therefore, it can be concluded that the test article formulation A did not show any irritating effect on the vaginal mucosa. The histopathological evaluation gave no local test article-related findings.

[0172] Example 15: Clinical performance in the treatment of bacterial vaginosis The clinical performance, tolerability and safety of Formulation A in the treatment of bacterial vaginosis in human patients was investigated in an open-label study. Patients with a confirmed bacterial vaginosis diagnosis were defined as having at least three of four of the following criteria: 1. Thin, white, yellowish, homogeneous secretion 2. Thread-like cells (more than 20% of epithelial cells) observed under a microscope Vaginal fluid pH greater than 3.4.5 4. Release of a fishy odor upon addition of alkali (10% potassium hydroxide [KOH] solution), "i.e., a positive whiff test."

[0173] Patients were included in the study if they had a confirmed bacterial vaginosis diagnosis on day 0. Patients self-administered Formulation A at 2-day intervals (days 0, 2, 4, and 6) and were examined for clinical cure rate on day 7, defined as the absence of all of criteria 1, 2, and 4 above. The number and disposition of patients are shown in Table 29.

[0174] Table 29. Number of patients (planned and analyzed) [Table 29]

[0175] Table 30. Statistical analysis of clinical cure rates on day 7. PPAS clinical cure. [Table 30]

[0176] Table 31. Statistical analysis of recurrence rates on days 14 and 35. Full analysis set. [Table 31]

[0177] Summary of efficacy results Primary Clinical Performance Endpoint (FAS): The clinical cure rate for Formulation A, defined as the absence of all three Amsel criteria, was 81.8% (one-sided 95% CI: 63.1%) at day 7, i.e., the primary performance objective of the study was met. See Table 30. Secondary Clinical Performance Endpoints (FAS): On day 7 compared to day 0, 85.7% were negative for Amsel criterion 1 (thin, white, yellow, homogeneous secretion; 90.0% for Amsel criterion 2 (thread-like cells (>20% of epithelial cells) on microscopic examination) and 86.4% for Amsel criterion 3 (emission of a fishy odor; i.e., positive Whiff test upon addition of alkali [10% KOH solution]). A 69.6% percentage had a reduction in the sum of 3 BV symptoms (fishy odor, burning, and irritation) on day 4 compared to day 0. On day 7 the percentage was 77.3%. · Analysis of ease of use, as measured by the patient questionnaire on day 7, showed that 87.5% of patients agreed that the vaginal tablet was easy to use, 75.0% found the use of the vaginal tablet to be gentle, 79.2% agreed that there was no odor during the treatment, and 62.5% of patients thought that the treatment did not stain or drip. Furthermore, responses to the question "What do you think of this treatment in general?" showed results at the high end of the scale (on a scale of 1 ["not satisfied"] to 10 ["very satisfied"], median: 8.0; mean: 7.1). The recurrence rate was 5.6% on day 14. That is, 1 of 18 patients who were clinically cured on day 7 reported a recurrence of symptoms on day 14. No further patients reported any recurrence by day 35, meaning the recurrence rate on day 35 was the same 5.6%. See Table 31.

[0178] Overview of safety evaluation Exposure level In total, 24 patients (100%) received the study treatment in this study. Based on information from patients when asked about dosing, over 95% of patients stated that they had administered the product at all planned time points in the study (days 0, 2, 4, and 6).

[0179] At baseline (day 0), the mean (SD) pH was 5.32 (0.50) and the mean (SD) pH was 4.84 (1.03) at day 7. A lower vaginal pH at follow-up evaluation is an indication of adequate release.

[0180] Summary of adverse events In total, 34 AEs were reported by 18 patients (75%) in this study. There were no deaths or SAEs in this study.

[0181] The most common AEs (preferred term) were headache (13 events in 10 patients, 41.7%) and dysmenorrhea (3 events in 3 patients, 12.5%).

[0182] Of the 34 AEs that occurred in this study, 6 AEs were judged to be related or possibly related to the study procedures, and 5 AEs were judged to be related or possibly related to the investigational device.

[0183] Most AEs were mild to moderate. Two patients had two severe AEs (8.3%): fever and peritonsillar abscess.

[0184] Overall conclusion The primary objective of the study was achieved, therefore the study provided evidence of both the clinical performance and a favorable safety / tolerability profile of Formulation A. Clinical treatment rates were high, no safety concerns were identified, Formulation A was well tolerated, and few AEs assessed as possibly related to the investigational device / Formulation A or study procedures were reported. No SAEs or device defects were reported during this study.

[0185] Example 16: Clinical performance in the treatment of vaginal candidiasis The clinical performance, tolerability and safety of Formulation A in treating vaginal candidiasis in human patients is examined in an open-label study. Patients with vaginal candidiasis have the following findings in addition to white or cream-colored vaginal discharge: At least two of the following signs and symptoms of VVC characterized as at least moderate: itching, burning, irritation, swelling, redness, or abrasion. · Potassium hydroxide (KOH) or saline preparations from inflamed vaginal mucosa or secretions revealing yeast morphology (hyphae or pseudohyphae) or Saccharomyces cerevisiae.

[0186] Patients with confirmed vaginal candidiasis will be included in the study on Day 0. Patients will self-administer Formulation A at 2-day intervals (Days 0, 2, 4, and 6) and will be examined for clinical cure on Day 7, defined as free of signs and symptoms of VVC, in terms of a Vulvovaginal Composite Signs and Symptoms (CVVS) score of 3 or less.

[0187] Each of the following six vulvovaginal signs and symptoms is scored separately using the scoring scale below and then added together to determine the CVVS score. Vulvovaginal signs: erythema, edema, or excoriation Vulvovaginal symptoms: Itching, burning, or irritation

[0188] Scoring scale: Each score needs to be objectively defined. 0=none (not present); 1=mild (slight); 2=moderate (definitely present); 3=severe (noticeable, intense).

Claims

1. 1. A solid pharmaceutical composition suitable for vaginal administration, comprising: a. 5-30 wt % glucono-δ-lactone (GDL); b. 10-40 wt % hypromellose (HPMC); and c. 10 to 30 wt % gluconate 1. A solid pharmaceutical composition comprising:

2. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is a tablet.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein 60% or less of the pharmaceutical composition dissolves within 2 hours at 50 rpm in 500 mL of 50 mM acetate buffer, pH 4.0 at 37° C. using the United States Pharmacopeia (USP) dissolution apparatus 2-paddle method.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein GDL is released in vivo for at least 6 hours, such as at least 12 hours, such as at least 18 hours, such as at least 24 hours, such as at least 36 hours, such as at least 42 hours.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the amount of GDL is between 50 and 500 mg, such as between 100 and 400 mg, such as about 150 mg or about 300 mg.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the composition comprises 10 to 25 wt% GDL, such as about 20 wt% or such as about 15 wt%.

7. The pharmaceutical composition of claim 1, wherein the gluconate is sodium gluconate (NaG).

8. 8. The pharmaceutical composition of claim 1, wherein the composition comprises NaG in the range of 15-25 wt%, 18-19 wt%, or 24-25 wt%.

9. 9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the molar ratio of GDL and gluconate is from 2:1 to 1:2, such as from 3:2 to 2:3, such as about 1:

1.

10. 10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the composition comprises HPMC in the range of 10 to 20 wt%, such as 20 to 35 wt%, or HPMC in the range of 15 to 40 wt%.

11. 11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the viscosity of the HPMC is in the range of 50 to 200 mPas, such as 100 mPas, or wherein the viscosity of the HPMC is in the range of 50,000 to 200,000 mPas, such as 100,000 mPas.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the composition further comprises starch, silica, a lubricant, and / or microcrystalline cellulose (MCC).

13. provided that the sum of the components does not exceed 100 wt. % of the composition; a. 10-25 wt% GDL; 15-30 wt% NaG; 10-40 wt% HPMC; 10-25 wt% starch; 0.25-1.25 wt% silica; and 0.5-1.5 wt% magnesium stearate; b. 10-25 wt% GDL; 10-30 wt% NaG; 5-40 wt% HPMC; 10-45 wt% MCC; 10-20 wt% starch; 0.25-1.25 wt% silica; and 0.5-1.5 wt% magnesium stearate, or c. 10-25 wt% GDL; 15-30 wt% NaG; 30-40 wt% HPMC; 15-45 wt% starch; 0.25-1.25 wt% silica; and 0.5-1.5 wt% magnesium stearate.

2. The pharmaceutical composition of claim 1, comprising or consisting of:

14. provided that the sum of the components does not exceed 100 wt. % of the composition; a. 15 wt% GDL; 18.4 wt% NaG; 15 wt% HPMC; 36 wt% MCC; 14.25 wt% starch; 0.38 wt% silica; and 1.0 wt% magnesium stearate, or b. 20 wt% GDL; 24.5 wt% NaG; 35 wt% HPMC; 19 wt% starch; 0.5 wt% silica; and 1 wt% magnesium stearate.

2. The pharmaceutical composition of claim 1, comprising or consisting of:

15. A pharmaceutical composition according to any one of claims 1 to 14 for use as a medicament.

16. A pharmaceutical composition according to any one of claims 1 to 15 for use in the treatment of a microbial infection, such as a vaginal microbial infection.

17. 17. Use of a pharmaceutical composition according to any one of claims 1 to 16 in the manufacture of a medicament for the treatment of a microbial infection, such as a vaginal microbial infection.

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