WO2024136769A1

WO2024136769A1 - Homogenously splittable tablet compositions comprising carglumic acid

Info

Publication number: WO2024136769A1
Application number: PCT/TR2022/051534
Authority: WO
Inventors: Erol KIRESEPI; Ersin Yildirim
Original assignee: Santa Farma Ilac Sanayi AS
Current assignee: Santa Farma Ilac Sanayi AS
Priority date: 2022-12-20
Filing date: 2022-12-20
Publication date: 2024-06-27
Anticipated expiration: 2025-06-20
Also published as: EP4637741A1

Abstract

The present invention relates to a homogenously splittable solid pharmaceutical composition comprising carglumic acid and a diluent in a particular amount range by the total weight of the composition along with at least one other pharmaceutically acceptable excipient manufactured by using a direct compression process.

Description

HOMOGENOUSLY SPLITTABLE TABLET COMPOSITIONS COMPRISING CARGLUMIC ACID

FIELD OF INVENTION

The present invention relates to a homogenously splittable solid pharmaceutical composition comprising carglumic acid and at least one pharmaceutically acceptable excipient manufactured by using a direct compression process.

STATE OF ART

Carglumic acid is an amino acid and structurally analog of N- acetylglutamate (NAG), which is the naturally occurring activator of carbamoyl phosphate synthetase (CPS) and helps to break down ammonia to reduce concentration in blood and toxic effects.

N- acetylglutamate (NAGS) synthase deficiency is one the most severe and rarest hereditary urea cycle disorders, resulting in a severe defect of ammonia detoxification with a rapid lethal course in most cases.

The urea cycle is the unique elimination pathway of ammonium. In the normal mitochondrion, NAG is the necessary allosteric activator of the CPS enzyme. NAG is produced by the NAG synthase (NAGS) from acetyl CoA and glutamate in the mitochondrion.

Carglumic acid is an amino acid analog of NAG, which is effectively transported unidirectionally in vivo out of mitochondria and is able to permeate the mitochondrial membrane easier than NAG, where it acts on CPS1. Thus, carglumic acid is essential for urea cycle function.

The chemical name of carglumic acid is N-carbamoyl- L-glutamic acid (NCGA) or (2S)-2- (carbamoylamino) pentanedioic acid. The molecular formula is C6H10N2O5 and the compound has a molecular weight of 190.16 g/mol. The structural formula of carglumic acid is shown in Formula I.

Carglumic acid is an acidic drug molecule in the form of a white crystalline powder having aqueous solubility of 19.1 mg/mL, and practically insoluble in organic solvents.

Carglumic acid and its biological activity were first described in 1952 in the publication of Grisolia S. et al.: J. Biological Chem. 1952, 198, 561-71. However, its acceptable salts thereof and therapeutically used in hyperammonaemia conditions were disclosed in GB 112347 numbered patent document.

The active substance has one chiral carbon in its structure atom and shows an optical isomer, which is N-carbamoyl-D-glutamic acid.

Commercially, a pharmaceutical drug product comprising carglumic acid as an active substance was first approved by the European Medicines Agency on January 2003 under the brand name CARBAGLU for indicating in the treatment of hyperammonaemia due to N- acetylglutamate synthase primary deficiency, hyperammonaemia due to isovaleric acidaemia, hyperammonaemia due to methymalonic acidaemia, and hyperammonaemia due to propionic acidaemia. The dispersible tablet dosage form of CARBAGLU is available as 200 mg tablets, which should be administered after dissolving water (minimum 5 - 10 ml per 200 mg tablet) either orally or through a nasogastric/gastrostomy tube. CARBAGLU is should be taken before meals or feedings and divided the total daily dose into two to four doses based on a half-life of 5 - 6 h, which is much longer than the half-life of NAG.

NAGS deficiency is a very rare inborn error of metabolism. Its estimated prevalence is 0.00125 per 10,000 per person in the European Union. Thus, CARBAGLU was designated as an orphan medicinal product in the treatment of this condition.

In the state of the art, there are limited patents/patent applications due to the rarity of hyperammonaemia disease, which are summarized below.

EP277769 relates to a pharmaceutical composition comprising 30% w/w to 50%w/w of carglumic acid, 40% w/w to 60%w/w of microcrystalline cellulose, and hydroxypropyl methylcellulose as cellulosic fillers, and at least one lubricant, wherein the composition is manufactured by direct compression method.

WO2018158249 relates to a stable pharmaceutical composition comprising carglumic acid as an active ingredient, lactose monohydrate as a binder, sodium croscarmellose as a disintegrant, colloidal silicon dioxide as a glidant, and hydrogenated castor oil as a lubricant, wherein the composition is manufactured by direct compression method.

The pharmacokinetics profile of carglumic acid was determined based on studies in 12 healthy male adult volunteers who each received a single oral administration of 100 mg/kg. Following single oral dose administration, carglumic acid peaks in plasma after a few hours; median of 3 hours (range: 2 - 4 h), with a concentration reaching a median of 2.6 pg/ml (range: 1.8 - 4.8 pg/ml). The rate of absorption was approximately 30%, while 5-9% of carglumic acid was excreted directly in the urine. Within 12 h after intake, approximately 70% of carglumic acid is lost through urine or feces, but small amounts can still be found after 96 h.

Carglumic acid is a chiral amino acid (L-isomer) with pKa values of 2.50, 3.55, and 8.60. In addition, it is stable in an alkaline medium (pH 10) but undergoes rapid degradation in a very acidic medium (pH 1).

The powder flowability of carglumic acid itself is poor. Thus, a homogenous powder blend should be generated to obtain a pharmaceutical composition comprising high drug load active substance. In addition, carglumic acid is slightly soluble in water and practically insoluble in organic solvents. Therefore, the excipients and the manufacturing method are the most important parameters to be considered to obtain an improved formulation with improved solubility and powder flow characteristics.

In conclusion, there is still a need to develop a tablet composition comprising carglumic acid as an active ingredient, and at least one pharmaceutically acceptable excipient that generate a homogenous powder blend by using direct compression method that overcomes flowability and solubility challenges originating from the characteristics of the active substance.

SUMMARY OF THE INVENTION

The object of this invention is to develop a homogenously splittable pharmaceutical composition comprising a therapeutically effective amount of carglumic acid and at least one pharmaceutically acceptable excipient by using direct compression method.

It is an object of the present invention is to develop a homogenous solid pharmaceutical composition comprising carglumic acid which is used in the treatment of hyperammonaemia. The present invention is to develop a homogenous solid composition comprising carglumic acid and at least one pharmaceutically acceptable excipient manufactured by using direct compression process.

Another object of the present invention is to develop preparation method of a pharmaceutical composition of carglumic acid wherein the pharmaceutical compositions herein disclosed can be manufactured into solid dosage forms, such as tablet, capsule, granule, powder.

Another object of the present invention is to develop a tablet dosage form comprising carglumic acid having three scores which maintain the tablets to be split into four equal parts and able to be administered the prescribed dose. The mentioned tablet splitting is performed by the patient. Therefore, it should be adjusted to act easily and get accurate repeatable results.

A “homogenously splittable tablet” definition is about tablets that have the ability to be split into an equal plurality of smaller dosage forms and improve the dose regimen for special patient populations.

Another object of the present invention is to develop a preparation method of a tablet composition of carglumic acid wherein the pharmaceutical compositions comprise a particular amount of carglumic acid in a particular range of particle size distribution.

Another object of the present invention is to develop a preparation method of a tablet composition of carglumic acid wherein the pharmaceutical compositions comprise a particular amount of mannitol as diluent in a particular range of particle size distribution (PSD).

Another object of the present invention relates to a homogenous solid pharmaceutical composition comprising mannitol with 90% ratio of the particle sizes (PSD value D90) within 100 - 200 micrometers range.

The amount range of manntiol in the composition is between 35-45% by the total weight of the composition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a homogenous solid formulation comprising carglumic acid as active ingredient.

Carglumic acid is used to treat and prevent hyperammonemia (too much ammonia in the blood) caused by the lack of a liver enzyme called N-acetylglutamate synthase (NAGS). It is also used to prevent hyperammonemia caused by certain genetic disorders called propionic acidemia (PA) or methylmalonic acidemia (MMA).

Carglumic acid is an orphan drug and a derivative of N- acetylglutamate that activates the first enzyme in the urea cycle that is responsible for removal and detoxification of ammonia, a valuable agent for therapy of hyperammonemia caused by rare forms of urea cycle defects.

In a preferred embodiment of the present invention is to provide a pharmaceutical composition for oral administration. Suitable solid oral dosage forms are selected from the group comprising tablet, capsule, granule, powder, preferably the solid oral dosage form is tablet.

Tablets comprising carglumic acid can be administered in low doses are convenient to be prescribed by splitting the tablets with the help of multiple scores on them.

In a preferred embodiment of homogenously divisible tablet composition, a diluent is designated for successful tablet compression and splitting.

In the preferred embodiment of the present invention, diluent may include, but are not limited to, dibasic calcium phosphate dihydrate, polysaccharides, primarily microcrystalline cellulose, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof. The most preferred diluent is mannitol.

In the preferred embodiment of a homogenous solid composition comprising carglumic acid, mannitol and at least one pharmaceutically acceptable excipient is manufactured by using direct compression method.

In the preferred embodiment of the present invention, the filler may include, but are not limited to dibasic calcium phosphate dihydrate, polysaccharides, microcrystalline cellulose, lactose and the like and mixtures thereof. Preferably, the filler is microcrystalline cellulose.

In the preferred embodiment of the present invention, the lubricant may include, but are not limited to magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, sodium stearyl fumarate, sodium lauril sulfate, glyceryl palmitostearate, and hydrogenated vegetable oils and fats, as well as other known lubricants. Preferably, the lubricant is sodium stearyl fumarate.

In the preferred embodiment of the present invention, the glidant may include, but are not limited to silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc and other known glidant. Preferably, the glidant is colloidal silicon dioxide. In the preferred embodiment of the present invention, the disintegrant may include, but are not limited to crospovidone, carboxymethylcellulose, methylcellulose, alginic acid, sodium starch glycolate, starch, formaldehyde. Preferably, the disintegrant is crospovidone.

In the preferred embodiment of the present invention, the binder may include, but are not limited to hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, ethylcellulose, methyl cellulose, hypromellose, povidone and copovidone. Preferably, the binder is copovidone.

The embodiment in accordance with the present invention was designed with adjusted quantitative composition composed of pharmaceutically acceptable ingredients mentioned above by using direct compression process.

The embodiment identified as Example 1 was given in the Table- 1 below.

The proposed embodiment based on the invention provides a solid pharmaceutical composition is as stated below:

Table 1: Unit Formula of Example 1

Another object of the present invention relates to provide direct compression process for preparing a pharmaceutical composition, providing the steps of: i. Carglumic acid was sifted through a proper sieve and then transferred into cubic mixer and stirred, ii. Croscarmellose sodium, microcrystalline cellulose, copovidone, crospovidone, colloidal silicon dioxide and mannitol were screened through a proper sieve and transferred into the same cubic mixer and stirred, iii. Sodium stearyl fumarate was sifted through a proper sieve and added to the powder blend prepared in Step (ii) and stirred to obtain a uniform final blend.

The flowability of final blend of Example 1 was investigated by performing analytical method in accordance with USP < 1174> the compressibility index and Hausner ratio correspond to the ratio of tapped density to bulk density.

The compressibility index and Hausner ratio were calculated as 27 and 1.36, respectively.

Scale of flowability;

Based on the results of scale of flowability, the final blend had “poor” flow characteristics. It was observed during the manufacturing that this was raised from carglumic acid active substance, because the appearance of carglumic acid was not homogenous due to its nature.

Example 2 was planned to be manufactured with the same formulation and direct compression method as it was in Example 1 with the only difference in the processing of carglumic acid which was processed to be sifted through a sieve with tightened pore sizes.

90% ratio of the particle sizes (D90) has a value of particle size distribution approximately 500 micrometres after sieving.

The flowability of final blend of Example 2 was investigated by performing analytical method in accordance with USP < 1174> the compressibility index and Hausner ratio correspond to the ratio of tapped density to bulk density.

The compressibility index and Hausner ratio were calculated as 18 and 1.22, respectively. Thus, based on the results the flowability characteristic was improved to “fair” from poor. The obtained tablets were subjected to an in-vitro dissolution study. The conditions of in-vitro dissolution study;

Dissolution medium : 0.1N HC1

Volume of dissolution medium : 500 ml

Temperature: : 37°C±0.5

Rotation speed : 50 rpm

Apparatus : Paddle

Duration of dissolution study : 60 minutes

Table 2: Comparison of dissolution profiles of Example-2 with reference drug product in 0.1N

HC1

Based on the results presented in Table 2 above, dissolution profiles of the reference product and Example 2 were quite similar based on the release profiles.

The appearance of tablets was designed to have three scores just to be able to administer as low doses. Moreover, the dose amount meant to be achieved after splitting should definitely be investigated. A uniformity of dosage units based on USP <905 > was performed to control the unity of the tablets to evaluate the homogeneity. The relative standard deviation of twenty tablets’ weight was 0.48 which means tablet compression with final blend was achieved successfully.

The physical appearance of the tablet is illustrated in Figure 1.

Therefore, the tablets should be splitted into three equal parts homogenously. The evaluation was performed by carrying out tablet many splits and observing each part. However, the tablets of Example-2 were not splitted into equal parts successfully.

The physical appearances of the splitted tablets are illustrated in Figure 2. It was an unexpected issue regarding not facing any negative issues during manufacturing and analytical testing. Therefore, this problem may raise from the direct compression method, because of no solvent used during manufacturing. It was a challenging issue to obtain a solution does not have negative impact on the proposed composition design, manufacturing method which gave positive analysis result presented above.

The first actions to move forward according the skilled person in the art would be changing the types and/or the amounts of binder and/or disintegrant. However, it would affect both composition and release profile most probably causes proposing many more formulations to regulate all the characteristics again, which were already obtained.

On the other hand, next embodiment was designed to keep constant the formulation and manufacturing method as Example-2 by using mannitol as the diluent with PSD values between 100 - 200 micrometers.

The flowability of final blend of Example 3 was investigated by performing analytical method in accordance with USP < 1174> the compressibility index and Hausner ratio correspond to the ratio of tapped density to bulk density.

The compressibility index and Hausner ratio were calculated as 18 and 1.21, respectively. Thus, based on the results the flowability characteristic was “fair”.

The obtained tablets were subjected to an in-vitro dissolution study.

Table 3: Comparison of dissolution profiles of Example-3 with reference drug product in 0.1N HC1

Based on the results presented in Table 3 above, dissolution profiles of the reference product and Example-3 were quite similar based on the release profiles. The appearance of tablets was designed to have three scores just to be able to administer as low doses. Moreover, the dose amount meant to be achieved after splitting should definitely be investigated. A uniformity of dosage units based on USP <905 > was performed to control the unity of the tablets to evaluate the homogeneity. The relative standard deviation of twenty tablets’ weight was 0.49 which means tablet compression with final blend was achieved successfully.

The tablets of Example-3 were splitted into equal parts successfully. The physical appearances of the splitted tablets are illustrated in Figure 3.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

1. A homogenously splittable tablet composition comprising carglumic acid, mannitol as diluent and at least one further pharmaceutically acceptable excipient manufactured by using direct compression process, wherein the mannitol has a particle size distrubition of D90 is from 100 to 200 micrometers, and the amount of mannitol is in the range of 35-45% by weight of the total tablet formulation.

2. A homogenously splittable tablet composition according to Claim 1, wherein at least one pharmaceutically acceptable excipient is selected from binder, disintegrant, glidant, filler and lubricant.

3. A homogenously splittable tablet composition according to claim 2, wherein the binder is selected from hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, ethylcellulose, methyl cellulose, hypromellose, povidone and copovidone and mixtures thereof.

4. A homogenously splittable tablet composition according to claim 2, wherein the disintegrant is selected from crospovidone, carboxymethylcellulose, methylcellulose, alginic acid, sodium starch glycolate, starch, formaldehyde and mixtures thereof.

5. A homogenously splittable tablet composition according to claim 2, wherein the glidant is selected from silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc and mixtures thereof.

6. A homogenously splittable tablet composition according to claim 2, wherein the filler is selected from dibasic calcium phosphate dihydrate, polysaccharides, microcrystalline cellulose, lactose and the like and mixtures thereof.

7. A homogenously splittable tablet composition according to claim 2, wherein the lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, sodium stearyl fumarate, sodium lauril sulfate, glyceryl palmitostearate, and hydrogenated vegetable oils and mixtures thereof.

8. A homogenously splittable tablet composition according to any one of the preceding claims; wherein the composition is:

9. A direct compression method for manufacturing homogenously splittable tablet composition comprising carglumic acid comprises the steps of; i. Carglumic acid is sifted through a proper sieve and then transferred into cubic mixer and stirred, ii. Croscarmellose sodium, microcrystalline cellulose, copovidone, crospovidone, colloidal silicon dioxide and mannitol are screened through a proper sieve and transferred into the same cubic mixer and stirred, iii. Sodium stearyl fumarate is sifted through a proper sieve and added to the powder blend prepared in Step (ii) and stirred to obtain a uniform final blend. iv. Tablet compression is performed with the final blend in step (iii).