WO2018158249A1

WO2018158249A1 - Room temperature stable pharmaceutical composition comprising carglumic acid

Info

Publication number: WO2018158249A1
Application number: PCT/EP2018/054808
Authority: WO
Inventors: Salvatore AGOSTINO GIAMMILLARI; Giuseppe Maccari
Original assignee: Dipharma SA
Current assignee: Dipharma SA
Priority date: 2017-02-28
Filing date: 2018-02-27
Publication date: 2018-09-07
Anticipated expiration: 2019-08-28

Abstract

The present invention relates to a highly room temperature stable drug dosage forms comprising a Carbamoyl Phosphate Synthetase 1 (CPS 1) activator susceptible to degradation, notably moisture-induced; and at least one pharmaceutically acceptable excipient.

Description

ROOM TEMPERATURE STABLE PHARMACEUTICAL COMPOSITION COMPRISING CARGLUMIC ACID

FIELD OF THE INVENTION

The present invention relates to highly room temperature stable drug dosage forms comprising a compound susceptible to degradation, notably moisture- induced, and at least one pharmaceutically acceptable excipient.

More specifically, the invention regards the Carbamoyl Phosphate Synthetase 1 (CPS l) activator TVcarbamyl-Zv-glutamic acid or carglumic acid, also known as carbaglu^®.

BACKGROUND OF THE INVENTION

Carglumic acid is a drug marketed by Orphan Europe SARL under the brand name Carbaglu^® and it is used to treat hyperammonaemia due to N- acetylglutamate synthase primary deficiency, isovaleric acidaemia, methymalonic acidaemia, and propionic acidaemia. It has been approved in Europe in January 2003 for the treatment of N-acetylglutamate synthetase (NAGS) deficiency and in June 2011 for the organic acidaemia. It has also been approved in US by FDA for the treatment of the sole NAGS deficiency.

The latter is an autosomal rare genetic disorder characterized by complete or partial lack of functionality of the enzyme NAGS leading to partial or complete loss of N-acetylglutamate (NAG) availability. CPS 1 is the enzyme catalyzing the first step in ureagenesis. Lack of NAG renders activation of CPS 1, the first enzyme involved in the urea cycle, impossible, and consequently leads to accumulation of a waste product of protein metabolism, the highly toxic ammonia. In healthy population, urea cycle involves a series of biochemical steps in which ammonia is finally converted to urea, this less toxic urea being then removed from the blood through the kidneys and the bladder as urine. Besides, secondary deficiency of NAGS also leads to the so-called organic acidemia, or organic aciduria. Isovaleric aciduria, propionic aciduria and methylmalonic aciduria (MMA) are inherited organic acidurias (OAs) in which impaired organic acid metabolism induces hyperammonaemia (Valayannopoulos V., et al., Orphanet Journal of ^'Rare Diseases, 2016, ϋ^32). Carglumic acid is known for its poor wettability properties, and consequently presence of a wetting agent in the formulation has so far been retained mandatory to confer to the tablets adequate physico-chemical properties. However, as evidenced in the Scientific Discussion issued in 2004 by the EMA Committee for Proprietary Medicinal Products (CPMP), it has been hypothesized that the presence of the wetting agent sodium lauryl sulfate in carbaglu® formulation was the cause of episodes of mild to moderate diarrhea. Indeed, on the website "www.carbaglu.net", diarrhea is mentioned as one of the most common adverse reactions observed upon medication with carbaglu®. Even if its amount is reported to have then been decreased in the commercial carbaglu®, the fact is that it is still present to an amount of 0.5 mg per tablet. This means that for a daily dose regimen of 100 mg/kg, a patient of 70 kg will consume 35 tablets corresponding to 17.5 mg of sodium lauryl sulfate. Since this medicine has to be taken during whole life, it appears desirable to identify formulation devoid of this ingredient, but still presenting adequate physico- chemical properties.

It is also well known, that one other problem of the actual drug formulation (i.e., Carbaglu® tablets) is its chemical stability. Indeed, Carbaglu® has to be stored in a refrigerator at a temperature ranging from 2°C to 8°C and after the first opening, the in-use stability is a single period of 1 month at a temperature not above 25°C, after which it must be discarded. It will be evident that such storage conditions have an impact in the distribution chain of the medicine, in terms of costs and also in terms of logistics for the patient.

A further shadow of carbaglu® appears to be the rather long time required for the tablets to disintegrate appropriately. If this slowness of dispersion could at a first sight appear as a compliance problem only, it could indeed become problematic should the drug be given not fully dissolved. The prescribing information does indeed emphasize the importance of not swallowing the tablets. EP2777696, filed in name of Navinta, LLC, even discloses that administering the tablets as whole or crushed may cause serious adverse effects to the brain or even cause death. Consequently, a formulation of carglumic acid tablets dissolving rapidly would be rather welcome by the doctor and patient communities.

EP2777696 claims an improved formulation for preparing a pharmaceutical composition of a high dosage of carglumic acid by direct compression or dry granulation. Said manufacturing process is alleged to confer to the formulation a higher stability as well as a more rapid disintegration of the tablets upon contact with water.

As known to the persons skilled in the art, if direct compression tableting can overcome some of the drawbacks of the wet granulation processes, said direct compression can be however challenging. Indeed, finding the appropriate excipient composition, both qualitatively and quantitatively may result highly difficult, above all when the tablet is a high dosage form.

Consequently, there is still a medical need of alternative formulations procuring less side-effects than the only approved one! as well as of alternative more stable formulations, both from a logistic supply chain point of view, and from the patient compliance point of view.

DESCRIPTION OF THE INVENTION

The present invention relates to a highly and durably stable pharmaceutical composition comprising crystalline A½arbamyl-Zv- glutamic acid, a filler, a disintegrant, a glidant, a lubricant, and optionally a wetting agent and/or a binder.

While not intending to be bound in any way by any theory, it is believed that the surprising improved chemical stability of

acid pharmaceutical composition of the present invention is attributable to the combination of the highly pure crystallinity of .V-carbamyl-Zv-glutamic acid in combination with a particular choice of excipients.

Development of carglumic acid pharmaceutical composition by means of direct compression started by selecting an appropriate combination of excipients, which ultimately led to batches of carglumic acid tablets possessing suitable hardness, friability, disintegration, appearance, average weight, moisture and assay properties. In one embodiment of the present invention, the pharmaceutical composition is for treating patients suffering from urea cycle disorders.

Generally, the pharmaceutical composition of the present invention is administered in a "therapeutically effective amount". The amount of the pharmaceutical formulation actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, any other potential drug the patient is currently taking, the age, the sex, body weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

Generally, an effective dose will be from 10 mg/kg, up to 250 mg/kg if necessary, preferably 10 mg/kg/day to 150 mg/kg/day. The daily dose is preferably given in two equal doses, or even more preferably up to four equal doses.

Dose adjustment will be made according to level monitoring of plasma ammonia. Suitable disintegrant can be chosen from the list comprising sodium croscarmellose, crospovidone, sodium starch glycolate, primellose®, and crosslinked alginic acid.

Unless otherwise mentioned, the expression "% w/w" refers to the percentage of a substance present in the pharmaceutical formulation on a weight by weight basis (i.e., lg/lOOg is equivalent to 1% w/w).

The expressions "highly stable" and/or "durably stable" mean that the chemical integrity of the active ingredient is of at least 95% after one month of storage of the drug dosage form at 25°C and 60% RH.

The expression "room temperature stable" means that after three months of storage of the drug dosage form at 25°C and 60% RH, or at 40°C and 75% RH, there is no more than 0.05% of any impurity detected by HPLC.

The expressions "drug dosage form", "pharmaceutical composition" and "pharmaceutical formulation" are to be considered synonymous in the context of the present invention.

In one embodiment,

acid crystals have a PSD (D90) between 130 to 240 μπι.

Another embodiment of the present invention consists of a crystalline pure N- carbamyl-Zv- glutamic acid Form A, which has a X-ray powder diffraction pattern with at least five specific peaks at about 2-theta = 15.45, 19.86, 21.83, 25.23, and 28.54, wherein said values may be plus or minus 0.2° 2-theta and have an intensity of at least 25%.

In a further embodiment of the present invention, the crystalline pure N- carbamyl-Zv- lutamic acid Form A has a X-ray powder diffraction pattern with at least ten specific peaks at about 2-theta = 15.45, 19.86, 21.83, 23.47, 25.23, 28.54, 31.24, 32.26, 34.8, 35.37, wherein said values may be plus or minus 0.2° 2-theta.

In one embodiment, said chemical integrity is of at least 96% after one month of storage of the drug dosage form at 25°C and 60% RH.

In another embodiment, said chemical integrity is of at least 97% after one month of storage of the drug dosage form at 25°C and 60% RH.

In a preferred embodiment, said chemical integrity is of at least 98% after one month of storage of the drug dosage form at 25°C and 60% RH.

In a still preferred embodiment, said chemical integrity is of at least 99% after one month of storage of the drug dosage form at 25°C and 60% RH.

Another embodiment of the invention contemplates chemical integrity of the drug dosage form after three months of storage at 25°C and 60% RH.

In said embodiment, the chemical integrity of the drug dosage form is of at least 95% after three months of storage of the drug dosage form at 25°C and 60% RH. In a preferred embodiment, the chemical integrity of the drug dosage form is of at least 96% after three months of storage of the drug dosage form at 25°C and 60% RH.

In another preferred embodiment, the chemical integrity of the drug dosage form is of at least 97% after three months of storage of the drug dosage form at 25°C and 60% RH.

In a still preferred embodiment, the chemical integrity of the drug dosage form is of at least 98% after three months of storage of the drug dosage form at 25°C and 60% RH.

In a still more preferred embodiment, the chemical integrity of the drug dosage form is of at least 99% after three months of storage of the drug dosage form at 25°C and 60% RH. Another embodiment of the invention contemplates chemical integrity of the drug dosage form after one month of storage at 40°C and 75% RH.

In said embodiment, the chemical integrity of the drug dosage form is of at least 95% after one month of storage of the drug dosage form at 40°C and 75% RH. In a preferred embodiment, the chemical integrity of the drug dosage form is of at least 96% after one month of storage of the drug dosage form at 40°C and 75% RH.

In another preferred embodiment, the chemical integrity of the drug dosage form is of at least 97% after one month of storage of the drug dosage form at 40°C and 75% RH.

In a still preferred embodiment, the chemical integrity of the drug dosage form is of at least 98% after one month of storage of the drug dosage form at 40°C and 75% RH.

In a still more preferred embodiment, the chemical integrity of the drug dosage form is of at least 99% after one month of storage of the drug dosage form at 40°C and 75% RH.

Another embodiment of the invention contemplates chemical integrity of the drug dosage form after three months of storage at 40°C and 75% RH.

In said embodiment, the chemical integrity of the drug dosage form is of at least 95% after three months of storage of the drug dosage form at 40°C and 75% RH. In a preferred embodiment, the chemical integrity of the drug dosage form is of at least 96% after three months of storage of the drug dosage form at 40°C and 75% RH.

In another preferred embodiment, the chemical integrity of the drug dosage form is of at least 97% after three months of storage of the drug dosage form at 40°C and 75% RH.

In a still preferred embodiment, the chemical integrity of the drug dosage form is of at least 98% after three months of storage of the drug dosage form at 40°C and 75% RH.

In a still more preferred embodiment, the chemical integrity of the drug dosage form is of at least 99% after three months of storage of the drug dosage form at 40°C and 75% RH. It is submitted that testing at 40°C and 75% RH for a short time such as three months, is considered indicative of stability at 25°C (i.e., room temperature) for a longer period of time (twelve months).

In a preferred embodiment, the disintegrant is sodium croscarmellose.

A suitable lubricant may be chosen from the list comprising stearic acid, magnesium stearate, hydrogenated castor oil, and sodium stearyl fumarate. In a preferred embodiment, such pharmaceutical composition comprises hydrogenated castor oil as lubricant.

A suitable filler may be chosen from the list comprising pregelatinized starch, microcrystalline cellulose, anhydrous lactose, lactose monohydrate and mannitol.

In a preferred embodiment, such pharmaceutical composition comprises lactose as a filler.

In a more preferred embodiment, said lactose is lactose monohydrate.

A suitable glidant may be colloidal silicon dioxide.

In a still more preferred embodiment, such pharmaceutical composition does not comprise any wetting agent.

In another embodiment the filler, disintegrant, glidant and lubricant are present in the final pharmaceutical composition at a concentration of between 48% to 59%, 3% to 6%, 0.25% to 0.70%, and 0.6% to 3% respectively, all concentrations being expressed as % w/w.

In a preferred embodiment the pharmaceutical composition comprises sodium croscarmellose, hydrogenated castor oil, lactose monohydrate and colloidal silicon dioxide.

EXAMPLES

Material used

Active pharmaceutical ingredient

Carglumic acid was obtained in pure crystalline form by reacting L- glutamic acid and potassium cyanate, according to known methods. Its chemical purity, calculated on anhydrous and solvent free basis, was assessed by means of HPLC at a wavelength detection of 205 nm. The product resulted 99.70% pure with no single impurities present in an amount greater than 0.03%. XRPD demonstrated that the crystalline form corresponded to Form-I disclosed by Maddileti D., et al, in CrystEngComm, 2015, 17, 5252.

Crystalline form of carglumic acid has been characterised by Bruker D8 Advance X-ray powder diffraction (XRPD), Bragg-Brentano geometry, CuKa radiation with wavelength λ = 1.54; scanning with 2Θ angle range of 3° to 40°, step size of 0.02° for 0.5 seconds per step. Linear solid-state detector (Lynx Eye).

Diluent

Pregelatinized starch: (Starch 1500®; Colorcon, Eighenmann & Veronelli) Macrocrystalline cellulose: Avicel PH102

Anhydrous lactose: Pharmatose DCL 21 (Eigenmann e Veronelli SPA)

Lactose monohydrate: Pharmatose DCL11 (Eigenmann e Veronelli SPA) Mannitol: Pearlitol 200SD (Roquette)

Lubricant

Stearic acid (Stearic acid 50, Carlo Erba)

Magnesium stearate (vegetal grade, Ligamed MF-3-V, Peter Greven Nederland) Hydrogenated castor oil: Cutina HR (Eurotrading SPA)

Sodium stearyl fumarate: PRUV® (JRS Pharma)

Disintegrant

Sodium croscarmellose: Ac-Di-Sol (IMCD Italia SPA)

Crospovidone: Kollidon® CL BASF

Sodium starch glycolate type A: Explosol® A Blanver:

FEASIBILITY EXAMPLES

Pharmaceutical formulations

The various excipients were tested for their compatibility with the carglumic acid in dry and wet conditions. 1/1 mixtures (w/w^: carglumic acid/single excipient) were made, and their stabilities analyzed at day 0 and at day 21.

From these preliminary stability studies, it emerged that pharmaceutical compositions comprising carglumic acid, lactose (i.e., anhydrous lactose or lactose monohydrate), sodium croscarmellose, colloidal anhydrous silica and hydrogenated castor oil resulted extremely stable. In order to assess the influence of particle size of the active pharmaceutical ingredient, 3 different grades of carglumic acid were used. Un-milled carglumic acid active ingredient (batch l) was milled by means of a hammer mill apparatus (Model RP 300, Nuova Guseo), applying variable hammer speed (i.e., 1500 or 3000 rpm) as well as varying cochlea speed (20 or 100 rpm), and using a 0.8 mm mesh screen.

Particle sizes are reported in table 1 underneath.

Table 1

Depending on the milling grade of carglumic acid in the below examples, either batch 1 (un-milled), 2 or 3 of Table 1 were used to obtain pharmaceutical compositions exemplified in examples 1 to 6, as described underneath.

Example 1

Pharmaceutical composition of example 1 was obtained following a manufacturing process comprising the following steps^

a) Mixing in a 5 liter stainless biconical tank for 10 min at 10 rpm, un-milled carglumic acid (600 g, batch l) and lactose monohydrate (805.50 g);

b) Add sodium croscarmellose (75 g) and colloidal anhydrous silica (4.50 g) and mix for 10 min at 10 rpm!

c) Add hydrogenated castor oil (15 g) and mix for 10 min at 10 rpm! and d) Compress the final mixture using Ronchi EA8 rotary tablet press equipped with 4 round flat punches, ø 11.9 mm with a compression force of between 30 to 35 KN.

Examples 2-6

Examples 2 to 6 were obtained following the process described in example 1, selecting the adequate ingredients of step a) as depicted in Table 2. Table 2

Analysis

Prior, to step d) of examples 1-6, the mixtures were sampled and titled for their content in carglumic acid in order to assess the influence of the particle size of carglumic acid ingredient as well as the impact of the nature of lactose filler on the homogeneity of the mixtures. The sampling points were selected considering the biconical geometry of the tank and height of the blend in said tank. Two samples for each blend were extracted, one at the bottom of the tank, and one at its top.

Homogeneity

Chemicals and reagents

Methanol HPLC grade

carglumic acid working standard

Chromatographic parameters

Column^ Atlantis T3 250 x 4.6 mm 5 Dm (or equivalent)

Mobile phase: 0.1% H3PO4 in H₂0 / Methanol = 95/5

Flow: 1.0 ml/min

Detector: 205 nm

Temperature: 30°C

Injection volume: 10 μΐ

Run Time: 10 minutes Analytical procedures

Standard solution

30.0 mg of carglumic acid working standard were accurately weighed into a 10.0 ml volumetric flask. Then 5.0 ml of water were added, and the solution was sonicated and further diluted with 5.0 ml of water.

Sample solution

150.0 mg of homogenized powder were accurately weighed into a 20.0 ml volumetric flask. 10.0 ml of water were then added, and the solution was sonicated for 10 minutes before being further diluted up to 20 ml.

Injection sequence

10 μΐ of water were injected and after 10 minutes, 10 μΐ of the standard solution was injected. The latter operation was repeated five times. The RSD value of five injections was always < 2.0%.

The assays were performed through 10 μΐ of sample solution injections.

Calculation for assay

The content of carglumic acid active ingredient was calculated according to equations 1 and 2 herein underneath:

A_s * W_std * Dil_s * T * M

Equation 1: C =

Astd * W_s * Dil_std

C

Equation 2: % active ingredient = * 100 where^

As = Area of active ingredient in the chromatogram of sample solution Astd = Average area of active ingredient in the chromatogram of standard solution

Wstd = Weight of working standard (mg)

Ws = Weight of sample (mg)

T = Assay of working standard (% / 100)

Dils = Sample dilution

Dilstd = Standard dilution

M = average weight of tablets

200.0 = theoretical content of active ingredient (mg) per tablet Table 3

As it is evident from the data reported in Table 3, no major deviation of carglumic acid content does appear among the various samples.

Mechanical properties

Table 4

NP: not per ormed

Reduction of particle size worsened slightly the flowability as can be seen from experiments derived from batches where carglumic acid had been milled.

Disintegration

Disintegration experiments have been performed following the protocol described in the European Pharmacopoeia (Ph. Eur.).

Table 5

As it would appear evident to the skilled person, pharmaceutical compositions comprising anhydrous lactose (examples 4-6) proved difficulties to disintegrate in a satisfying manner, meanwhile lactose monohydrate gave rise to suitable disintegration time, similar or even better than the one reported in EP2777696. Stability studies

In the Scientific discussion document referring to Carbaglu® issued by EMA in 2004, few impurities were reported: hydantoin- 5 -propionic acid, diaza-l,3^_dione- 2,4-carboxy7-cycloheptane, and 7V-carbamoyl-Z> glutamic acid. This document also mentioned that "unidentified substances appear only under stress conditions to which the active substance or the finished product is never subjecf.

After accelerated storage conditions, it was possible to identify 3 main impurities which were characterized as follows^:

Tablets from the six examples were stored at three different atmospheric conditions (i.e., temperature and Relative Humidity (RH)) as reported underneath.

• Condition 1 (refrigerated stability study): 5°C/

• Condition 2 (long-term stability study): 25°C/60%RH

· Condition 3 (accelerated stability study): 40°C/75%RH

Appropriate analytical methods were developed to fully assess the impurity profile of the pharmaceutical formulations at various time points as reported underneath.

Analytical methods

Column: Atlantis T3 250 x 4.6 mm 5 μηι (or equivalent)

Eluent A: Methanol

Eluent B: 0.1% H3PO4 in H₂0/methanol: 95/5

Flow^: 1.0 ml/min

Detector: 205 nm

Temperature: 30°C

Injection volume: 25 μΐ

Run Time^: 25 minutes

Post run: n

Carglumic acid:

Impurity l: 3^_(i?,_*¾⁾-[3-(aminocarbonyl)-2,5-dioxoimidazolidin-4-yl]-propanoic acid

Impurity 2- 3-(_*S)-(2,5-dioxoimidazolidin-4-yl)-propanoic acid Impurity 3^: 5-(i?)-oxopyrrolidine^_2-carboxylic acid

Surprisingly, enantiomer N- carbamoyl-∑ glutamic acid and diaza-l,3"dione-2,4- carboxy-7-cycloheptane, and A½arbamoyl-Z>glutamic acid were not detected in the pharmaceutical composition of the present invention.

Gradient:

Reference solution 0.03%

10.0 mg of carglumic acid working standard and 10.0 mg of each impurity were weighed out in a 100.0 ml volumetric flask and 50 ml of water was added. The resulting solution was sonicated and further diluted up to 100 ml with water. Sample solution

The sample solution was prepared as previously described after having powdered the tablets.

Injection sequence

25 μΐ of water were injected and after 37 minutes, 25 μΐ of the reference solution was injected. The latter operation was repeated five times. The RSD value of five injections was always < 5.0%.

The quantification of related substances was performed through 25 μΐ of sample solution injections.

Calculation for purity

The content of each impurity 1, 2 or 3 was calculated according to equation 3.

A_s * 0.2

Equation 3: / (%) =— where^

As = Area of impurity in the chromatogram of sample solution

ARef = Average area of Impurity 1 or Impurity 2 or Impurity 3 in the chromatograms of the Reference solution

0.2 = dilution factor

The content of any unknown impurity was calculated according to equation 4. A_s * 0.2

Equation 4: / (%) =— where^

As = Area of each unknown impurity in the chromatogram of sample solution

ARef = Average area of carglumic acid in the chromatogram of the

Reference solution

0.2 = dilution factor

Table 6

As evidenced in Tables 7- 9, pharmaceutical compositions comprising N- carbamyl-Zv- glutamic acid obtained through the process of the invention resulted extremely stable even in accelerated conditions for a period of at least three months.

Table 7

Table 8

Table 9

Claims

1. A room temperature stable solid pharmaceutical composition comprising N- carbamyl-Zv- glutamic acid as a pharmaceutically active ingredient, a diluent, a disintegrant, a glidant and a lubricant.

2. The room temperature stable solid pharmaceutical composition according to claim 1, characterized in that it does not contain any wetting agent.

3. The room temperature stable solid pharmaceutical composition according to claim 1 or claim 2, wherein the diluent, the disintegrant, the glidant and the lubricant are lactose (i.e., anhydrous lactose or lactose monohydrate), sodium croscarmellose, colloidal anhydrous silica and hydrogenated castor oil respectively.

4. The room temperature stable solid pharmaceutical composition according to any of claim 1 to 3, wherein TVcarbamyl-iy-glutamic acid is in crystalline Form A, wherein said crystalline Form A has a X-ray powder diffraction pattern with at least five specific peaks at about 2-theta = 15.45, 19.86, 21.83, 25.23, and 28.54, and wherein said values may be plus or minus 0.2° 2-theta and have an intensity of at least 25%.

5. The room temperature stable solid pharmaceutical composition according to claim 4, wherein

acid has a X-ray powder diffraction pattern with at least ten specific peaks at about 2-theta = 15.45, 19.86, 21.83, 23.47, 25.23, 28.54, 31.24, 32.26, 34.8, 35.37 wherein said values may be plus or minus 0.2° 2-theta.

6. The room temperature stable solid pharmaceutical composition according to any of claim 1 to claim 5, wherein the amount of disintegrant represents from 3% to 6% w/w of the total amount of the ingredients.

7. The room temperature stable solid pharmaceutical composition according to any of claim 1 to claim 6, wherein the diluent is lactose monohydrate.

8. The room temperature stable solid pharmaceutical composition according to any one of claims 1 to 7, wherein the chemical integrity of .V-carbamyl-Zv- glutamic acid is of at least 95% after three months of storage 25°C, more preferably of at least 97% after three months of storage 25°C, even more preferably of at least 98% after three months of storage 25°C, still even more preferably of at least 99% after three months of storage 25°C.

9. The room temperature stable solid pharmaceutical composition according to any one of claims 1 to 8, wherein the amount of the main impurity does not exceed 0.20% after 3 months of storage at 40°C/75%RH.

10. The room temperature stable solid pharmaceutical composition according to any one of claims 1 to 9 in the form of a tablet, wherein the amount of N- carbamyl-Zv- glutamic acid is typically 200 mg.

11. The room temperature stable solid pharmaceutical composition according to any one of claims 1 to 10 in the form of a tablet, wherein said tablet disintegrates in less than 30 seconds when in the presence of water.

12. The room temperature stable solid pharmaceutical composition according to claim 11 for treating patients affected by urea cycle disorder.