Rectal administration of carglumic acid

Abstract

The present invention relates to a composition comprising carglumic acid and sodium acetate. The invention further relates to the composition of the invention for treating hyperammonemia, more specifically N-Acetylglutamate synthase deficiency. The invention further relates to the composition comprising carglumic acid and sodium acetate, wherein the composition is formulated for rectal administration.. The invention also relates to the composition comprising carglumic acid and sodium acetate, wherein the rectal formulation is a suppository and wherein the suppository comprises polyethylene glycol (PEG) being a mixture of one or more low-molecular weight PEGs and one or more medium-molecular weight PEGs.

Description

[0001] RECTAL ADMINISTRATION OF CARGLUMIC ACID

[0002] The present invention relates to a composition comprising carglumic acid for treating hyperammonemia, more specifically N- Acetylglutamate synthase deficiency. The invention further relates to rectal administration of carglumic acid.

[0003] Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. Disorders leading to an excess of ammonia (hyperammonemia) can lead to brain injury and even death. Hyperammonemia is a rare hereditary disorder and thus considered one of the more severe metabolic diseases. It can occur due to several physical disorders, among which is N-acetyl glutamate synthase deficiency.

[0004] N-Acetyl glutamate synthase deficiency is an autosomal recessive urea cycle disorder and symptoms of this disorder already show within the first week of life of newborns. An infant with this condition may be lacking in energy (lethargic) or unwilling to eat and have difficulty controlling his or her breathing rate or body temperature. Severely affected babies may experience seizures or unusual body movements or go into a coma. Without any direct diagnosis and treatment, the complications of N-acetylglutamate synthase deficiency may include developmental delay and intellectual disability.

[0005] N-Acetyl glutamate is synthesized from acetyl-CoA and glutamic acid in the reaction catalyzed by N-acetyl glutamate synthase and plays a vital role in the urea cycle. Deficiency in N- acetyl glutamate synthase or a genetic mutation in the gene coding for the enzyme, will lead to urea cycle failure in which ammonia is not converted to urea, and therefore accumulated in blood.

[0006] Currently, there is no cure for hyperammonemia induced by N-acetylglutamate synthase deficiency. Treatment of this disorder includes administration of carglumic acid, an analogue of N- acetyl glutamate. Carglumic acid ((5')-2-ureidopentanedioic acid) can take the place of N-acetyl glutamate in the urea cycle, when it is administered as a medicament, however this compound merely mitigates the intensity of the disorder. Known hyperammonemia medicaments comprise for example Carbaglu® and Ucedane® tablets

[0007] Carglumic acid is an orphan drug administered via orodispersible tablets. However, when carglumic acid is administered orally, a large proportion of carglumic acid metabolites are excreted in the feces and urine, and a proportion of carglumic acid is suspected to be metabolized by the intestinal bacterial flora. Carglumic acid metabolites are primarily excreted via exhaled carbon dioxide. This administration route results in a bioavailability of maximally 30%. Furthermore, dissolving carglumic acid in water, results in a solution having a pH between 2 and 3, which solution tastes unpleasantly acidic and / or sour. Additionally, oral administration of potentially larger numbers of tablets taken orally per day may impair therapy adherence, especially for children. Furthermore, oral tablets may result in unwanted side effects such as vomiting, abdominal pain, diarrhea and headache. Oral administration of carglumic acid is thus considered unpleasant, in particular for children who are very sensitive to the unpleasant taste of the medicine. As hyperammonemia caused by of N-acetylglutamate synthase deficiency is a lifelong disorder that often already presents itself within weeks after birth, patients suffering from this disorder have to take the carglumic acid from birth for their entire lives. Therefore, there exists a need for new therapeutic administration of carglumic acid with less adverse side effects and taste, especially for newborn and young children.

[0008] It is therefore an objective of the invention to improve administration, of carglumic acid.

[0009] This objective is achieved by a composition comprising carglumic acid and sodium acetate.

[0010] It was found according to the invention that, when a composition of carglumic acid and sodium acetate is dissolved in water, the pH of the solution increases towards pH neutrality. Sodium acetate has a pKa of 4.54 and therefore has a buffering effect on carglumic acid in a solution. Due to this buffering effect, the combination of carglumic acid and sodium acetate, when administered to humans, does not lead to exposure of the surrounding tissue to the, potentially irritating and unpleasant, low pH of carglumic acid. A composition comprising carglumic acid and sodium acetate therefore provides an improvement over administration of carglumic acid without sodium acetate.

[0011] Since the pH of the solution of the composition comprising carglumic acid and sodium acetate is more acceptable for human tissue, said composition is thus more appropriate for pharmaceutical products. The invention therefore further relates to a pharmaceutical composition comprising carglumic acid and sodium acetate and optionally a pharmaceutically acceptable carrier and / or excipient.

[0012] The known medical application of carglumic acid can thus be enhanced by administering carglumic acid together with sodium acetate. The invention thus further relates to a composition comprising carglumic acid and sodium acetate for use as a medicament.

[0013] Since carglumic acid is a medicament for treating hyperammonaemia, the invention further relates to the composition comprising carglumic acid and sodium acetate for use as a medicament for the treatment of hyperammonaemia.

[0014] Carglumic acid is in particular a suitable medicament for treating hyperammonaemia when this disorder is the result N-acetylglutamate synthase deficiency. The invention thus further relates to the composition comprising carglumic acid and sodium acetate for use as a medicament for treatment of hyperammonaemia, wherein the hyperammonaemia is the result of N-acetylglutamate synthase deficiency.

[0015] Suitably, the invention relates to the composition comprising carglumic acid and sodium acetate, wherein the composition is formulated for use in rectal administration. When carglumic acid is orally administration it passes the gastrointestinal tract before it is absorbed in the blood. In the gastrointestinal tract carglumic acid is metabolized and therefore maximally 30% bioavailability of carglumic acid is achieved when orally administered. Rectal administration of this carglumic acid bypasses not only the gastrointestinal tract but also bypasses around two thirds of the first-pass metabolism as the rectum's venous drainage is two thirds systemic (middle and inferior rectal vein) and one third hepatic portal system (superior rectal vein). Furthermore, due to the absence of enzymes in the rectum, rectal degradation of drugs is relatively low and the presystemic loss due to metabolism by microorganisms in the rectum is generally considered to be non-significant. This means the drug will reach the circulatory system with significantly less alteration and in greater concentrations when the drug is rectally administered. The rectum itself is about 15 to 20 cm long in adults, whereas the length in children ranges from 3 to 12 cm depending on the age. Similarly, the average rectal surface area in adults is reported to be around 200-400 cm2whereas in children the area ranges from 18 to 230 cm2in one month of age to 10 years of age respectively. In addition, the pH differs in the different age groups and has a mean value of 7.2-7.4 in adults, 6.47 in neonates and 6.90 in older infants (> 28 days of age). The rectal fluid is relatively constant and has an average volume of 1-3 ml

[0016] However, direct administration of carglumic acid in the rectum acidifies the rectal environment to such a low pH that tissue damage occurs, complicating the rectal administration of carglumic acid. Therefore, according to the invention, carglumic acid is administered together with sodium acetate. Sodium acetate is a buffering agent which, when a composition comprising carglumic acid and sodium acetate is dissolved in water, causes the pH of the resulting solution to be physically acceptable, and preferably physically acceptable in the rectal environment. In the research leading to this invention it was demonstrated that rectal administration of carglumic acid and sodium acetate results in a higher bioavailability of carglumic acid of at least more than 30%, likely 35-40%, more preferably at least 50%, compared to orally administered carglumic acid than when carglumic acid is administered orally. As such, rectal administration of carglumic acid can lead to an increased therapeutic effect with a similar dose, requiring fewer individual administrations and increased patient comfort, especially for newborn and young children.

[0017] Suitable formulations for rectal administration are a suppository, enema or foam. The invention therefore relates to a composition comprising carglumic acid and sodium acetate formulated as a suppository, enema or foam. When a suppository comprising the composition of the invention is administered rectally, the suppository melts in the rectal wall together with about 3 ml of liquid. The composition comprising carglumic acid and sodium acetate dissolves in this liquid and can subsequently enter the bloodstream.

[0018] Several different ingredients can be used to form the base of a suppository: cocoa butter or a similar substitute, hydrogels, glycerinated gelatin, and polyethylene glycol. The type of material used depends on the type of suppository, the type of drug, and the conditions in which the suppository will be stored. It was found that when the carglumic acid of the composition of the invention is formulated in suppositories having a fat, hydrophobic basis, carglumic acid is not properly released from the suppository. It thus appears that the composition is not suitable to be administered in a suppository having a fat, hydrophobic basis. Therefore, in an embodiment of the invention, the rectal formulation is a suppository, and the suppository comprises polyethylene glycol (PEG).

[0019] Suppositories having a PEG basis are hydrophilic, water soluble and the solution of the compounds are not dependent on the melting behavior based on temperature. Suppositories having a PEG basis are therefore more temperature-resistant and therefore more suitable in countries having a warm climate, more stable during transport and do not have to be stored in a low- temperature environment.

[0020] In the context of the present invention, PEG may be followed by a number which represents the average molecular weight. This average molecular weight is calculated based on size distribution and can be characterized statistically by its weight average molecular weight (Mw). In the context of the present invention the Mwis defined as the “molecular weight”. The molecular weight of PEGs is further grouped as low, medium and high-molecular weight PEGs. A low- molecular weight PEG is a PEG in the range of PEG- 100 to PEG-600. A medium-molecular weight PEG is a PEG in the range of PEG- 1000 to PEG- 10000. A high-molecular weight PEG is a PEG in the range of PEG- 10000 and higher.

[0021] It was further found that the suppositories having a base of a mixture of low and medium- molecular weight PEGs are able to release the composition of the invention properly. Up to 100% of the composition of the invention was recovered from a suppository when the suppository has a basis of a mixture of low and medium-molecular weight PEGs. In one aspect, the invention thus relates to the composition of the invention comprised in a suppository comprising PEG, wherein the PEG is a mixture of one or more low-molecular weight PEGs and one or more medium- molecular weight PEGs.

[0022] The invention further relates to the composition comprised in a PEG-based suppository wherein the one or more low-molecular weight PEG is a PEG in the range of PEG- 100 to PEG- 600, preferably PEG-200 to PEG-500, more preferably PEG 300 to PEG-450, most preferable wherein the one or more low-molecular weight PEG is PEG-400. The low-molecular weight PEG is present to facilitate a more optimal dissolving rate of the suppository. In vivo carglumic acid becomes more biologically available when using suppositories comprising low-molecular weight PEGs.

[0023] Also, the invention relates to the composition comprised in a PEG-based suppository, wherein the one or more medium-molecular weight PEG is a PEG in the range of PEG- 1000 to PEG-10000, preferably PEG-2000 to PEG-8000, more preferably PEG-3000 to PEG-7000, most preferable wherein the one or more medium-molecular weight PEG is PEG-4000 and optionally PEG-6000. The medium-molecular weight PEG, in particular PEG-4000 is present to optimize the osmotic properties by attracting more liquid to the rectum. Active and potential diffusion to the wall of the rectum is increased when more liquid is present in the rectum. Additionally, the medium-molecular weight PEG, in particular PEG-6000 is present to obtain a more robust suppository.

[0024] A preferred embodiment of the invention is the composition of the invention comprised in a PEG-based suppository, wherein the PEG is a mixture of a PEG-400, PEG-4000 and PEG-6000.

[0025] In this preferred embodiment, PEG-6000 can be present in 20 to 60 wt.%, PEG-400 can be present in 10 to 40 wt.% and PEG-4000 can be present in 10 to 30 wt.% with respect to the total amount of PEG. Preferably PEG-6000 is present in about 45 wt.%, PEG-400 is present in about 25 wt.% and PEG-4000 is present in about 20 wt.% with respect to the total amount of PEG.

[0026] A further aspect of the invention is the composition of the invention comprised in a PEG- based suppository, wherein PEG is Macrogol 1500.

[0027] The composition of the invention may further comprise polysorbate 80 or Tween 80. This is a surfactant which usually is added to suppositories in 0.1 to 0.2 %. However, it was found that when polysorbate 80 (Tween 80) is added to the suppository in 0.1 to 0.2% and the suppository is subsequently administered to a subject, the subject may experience defecation issues. In a preferred embodiment of the invention, the composition of the invention is comprised in suppository which comprises between 0.001 % and 0.1 % polysorbate 80, preferably between 0.005 % and 0.05 % polysorbate 80, more preferably between 0.01 % and 0.02 % polysorbate 80, most preferably 0.015% polysorbate 80. When the polysorbate 80 is added to the suppository comprising the composition of the invention, the release of carglumic acid upon administration is enhanced, by decreasing the surface tension, by facilitating optimal dissolving the carglumic acid and by increasing the plasticity of the suppository mass when pouring out the suppositories.

[0028] The suppository comprising the composition of the invention can also comprise sodium lauryl sulphate. Preferably the composition of the invention is comprised in suppository which comprises between 0.001 % and 0.1 % sodium lauryl sulphate, preferably between 0.005 % and 0.05 % sodium lauryl sulphate, more preferably between 0.01 % and 0.02 % sodium lauryl sulphate, most preferably 0.015% sodium lauryl sulphate. Sodium lauryl sulphate in suppositories comprising the composition of the invention, also facilitates the release of carglumic acid upon administration, by decreasing the surface tension, by facilitating optimal dissolving the carglumic acid and by increasing the plasticity of the suppository mass when pouring out the suppositories.

[0029] Also, the composition of the invention may comprise colloidal silica, preferably hydrophilic fumed silica having a specific surface area of 200 m2 / g, such as Aerosil 200. Preferably colloidal silica is present in between 0.001 and 0.001 %. The presence of colloidal silica, preferably hydrophilic fumed silica prevents agglomeration of the contents of the suppository, in particular agglomeration of carglumic acid.

[0030] The buffering effect of sodium acetate can be achieved when carglumic acid and sodium acetate are present in a weight ratio in which the sodium acetate is able to increase the pH of the solution in which a composition comprising carglumic acid and sodium acetate is dissolved. The invention thus relates to the carglumic acid and sodium acetate being present in the composition in a weight ratio of carglumic acid / sodium acetate between 10 / 1 and 1 / 100, preferably between 5 / 1 and 1 / 50, more preferable between 1 / 1 and 1 / 10, even more preferably between 1 / 1 and 1 / 5, and most preferable 1 / 3.

[0031] The recommended pediatric maintenance daily oral dosage of carglumic acid is 10 mg / kg to lOOmg / kg. However, due to the increased bioavailability, the pediatric daily dosage of carglumic acid for rectal administration is 5-10 mg / kg, preferably 5-7.5 mg / kg most preferably 5 mg / kg. Suitably, the invention relates to one dosing unit of the composition comprising carglumic acid and sodium acetate comprising between 1 and 200 mg carglumic acid, preferably between 1 and 100 mg carglumic acid, most preferably between 25 and 50 mg carglumic acid.

[0032] The presence of sodium acetate in the composition comprising carglumic acid and sodium acetate can vary between 1 mg and 400 mg. According to the invention, the composition comprising carglumic acid and sodium acetate thus comprises between 1 and 400 mg sodium acetate, preferably between 50 and 200 mg sodium acetate, most preferably between 75 and 150 mg sodium acetate.

[0033] The presence of sodium acetate in the composition of the invention thus enables the rectal administration of carglumic acid. Rectal administration improves the bioavailability of carglumic acid over oral administration. The invention therefore further relates to the composition of the invention wherein the bioavailability of carglumic acid, is more than 30 %, preferably more than 40 %, even more preferably more than 50 %, most preferably more than 60 %.

[0034] Carglumic acid and sodium acetate are present in the composition of the invention in a weight ratio such that when said composition is dissolved in water, the pH of the resulting solution is pH between 3.5 and 7.5, preferably between 4.5 and 6.5, more preferably 5.5. The sodium acetate in the solution causes a buffering effect on the carglumic acid. This buffering effect thus causes that said resulting solution has a pH which is physiologically acceptable for the rectal environment and that the bioavailability of the carglumic acid is increased.

[0035] The composition comprising carglumic acid and sodium acetate can be administered to humans. The invention thus further relates to the composition comprising carglumic acid and sodium acetate being formulated for human subjects. Tablets comprising carglumic acid which are suspended in water have a very acidic and sour taste. Children who are in need of treatment with carglumic acid due to hyperammonaemia caused by N-acetyl glutamate deficiency often resist to this oral administration because of its unpleasant taste and unwanted side effects such as vomiting, abdominal pain, diarrhea and headache. The rectal administration of the composition comprising carglumic acid and sodium acetate is thus in particular suitable for newborns / neonates, infants and toddlers. The invention thus relates to a composition comprising carglumic acid and sodium acetate which is formulated for human subjects which are 0 to 10 years old, preferably 0 to 5 years old, more preferably 0 to 3 years old.

[0036] The invention further relates to a method for preparing the composition comprising carglumic acid and sodium acetate, comprising mixing therapeutically active amounts of carglumic acid and sodium acetate and optionally a pharmaceutically acceptable carrier and / or excipient.

[0037] Sodium acetate can be present in the form of sodium acetate trihydrate and anhydrous sodium acetate. Mixing sodium acetate trihydrate with therapeutically active amounts of carglumic acid may cause clumping. The invention therefore relates to the above method for preparing the composition of the invention, wherein sodium acetate is anhydrous sodium acetate.

[0038] Furthermore, the invention further to a method for preventing and / or treating hyperammonaemia, comprising the administration of a composition comprising carglumic acid and sodium acetate.

[0039] Additionally, the invention relates to a method for preventing and / or treating N- acetylglutamate synthase (NAGS) deficiency, comprising the administration of a composition comprising carglumic acid and sodium acetate.

[0040] In the context of this application the definition of the term ’’weight ratio” is the ratio between the amounts in weight of any two compounds present in a composition.

[0041] In the context of this application, the definition of “buffering effect” and “pH neutralizing effect” can be used interchangeably and should be interpreted such that a compound having a buffering effect can absorb H+and OH“ ions, thereby preventing large changes in pH when appreciable amounts of strong acid or base are added to a solution.

[0042] In the context of this application the definition of “physiologically acceptable pH for the rectal environment” should be interpreted as a pH level which does not cause damage to the tissue of the rectal environment.

[0043] The “rectal environment” should be interpreted as the area which comprises the anal canal and the rectum.

[0044] The present invention will be illustrated in the Examples that follow and that are not intended to limit the invention in any way. EXAMPLE

[0045] Example 1

[0046] In experiments, 1.15 mL mold suppository formulations were manufactured with CA 50 mg and sodium acetate trihydrate in a ratio by weight of 1:2, 1:3 and 1:4. Additionally 2.3 mL mold suppositories were manufactured with CA 100 mg and sodium acetate trihydrate in a ratio by weight of 1:3.

[0047] Solubility and pH experiments were conducted in 3mL purified water (pH 7) and water / citrate buffer (pH 6) at 37°C and in 900 mL citrate buffer (pH 6). Addition of sodium acetate trihydrate in the three ratios yielded in water a pH of 4.0, 4.5-5.0 and 4.5-5.0, respectively (table X). In citrate buffer all three ratios resulted in a pH of 5.5. These results confirmed an optimized CA to buffer ratio of 1:3. The 2.3 mL suppository containing 100 mg Ca was tested in 3mL water and citrate buffer and after dissolution, pH levels of 4.5-5.0 and 5.0 were found.

[0048] Table X. Results representing the pH after suppository dissolution in water and buffer media. An optimal CA to buffer ratio of 1 :3 was confirmed.

[0049] Example 2: Testing release of carglumic acid in suppositories compositions

[0050] The following suppository compositions were analyzed:

[0051] Suppository having a fat (Witepsol H15) basis:

[0052] Suppository having a PEG basis:

[0053] Dissolving the suppository to analyze Carglumic acid recovery: In a IL container 900 mL of purified water is added, 0.4 mL of trifluoroacetic acid and make up to volume with purified water. A suppository comprising 25 mg and a suppository comprising 50 mg carglumic acid were dissolved in the solution. Carglumic acid was recovered by extraction and analyzed by HPLC-UV.

[0054] Recovery of Carglumic from suppositories having a fat matrix:

[0055] Recovery of Carglumic acid from suppositories having a PEG matrix:

Claims

CLAIMS1. Composition comprising carglumic acid and sodium acetate.

2. Pharmaceutical composition comprising the composition as claimed in claim 1 and a pharmaceutically acceptable carrier and / or excipient.

3. Composition as claimed in claim 1 or 2 for use as a medicament.

4. Composition as claimed in claim 3, wherein the medicament is for treatment of hyperammonaemia.

5. Composition as claimed in claim 4, wherein the hyperammonaemia is the result of N- acetylglutamate synthase (NAGS) deficiency.

6. Composition as claimed in claim 1-5, wherein the composition is formulated for use in rectal administration.

7. Composition as claimed in claim 6, wherein the rectal formulation is a suppository, enema or foam.

8. Composition as claimed in claim 7, wherein the rectal formulation is a suppository and wherein the suppository comprises polyethylene glycol (PEG).

9. Composition as claimed in claim 8, wherein the PEG is a mixture of one or more low- molecular weight PEGs in the range of PEG- 100 to PEG-600 and one or more medium-molecular weight PEGs in the range of PEG- 1000 to PEG- 10000.

10. Composition as claimed in claim 9, wherein the one or more low-molecular weight PEG is a PEG in the range of PEG-200 to PEG-500, preferably PEG 300 to PEG-450, and more preferable wherein the one or more low-molecular weight PEG is PEG-400.

11. Composition as claimed in claim 9 or 10, wherein the one or more medium-molecular weight PEG is a PEG in the range PEG-2000 to PEG-8000, preferably PEG-3000 to PEG-7000,and most preferable wherein the one or more medium-molecular weight PEG is PEG-4000 and optionally PEG 6000.

12. Composition as claimed in claim 8 or 9, wherein PEG is Macrogol 1500.

13. Composition as claimed in claim 1-12, wherein the composition further comprises polysorbate 80, sodium lauryl sulphate and / or colloidal silicas.

14. Composition as claimed in any one of claims 2-13, wherein the weight ratio of carglumic acid / sodium acetate in the composition is between 10 / 1 and 1 / 100, preferably between 5 / 1 and 1 / 50, more preferable between 1 / 1 and 1 / 10, even more preferably between 1 / 1 and 1 / 5, and most preferable 1 / 3.

15. Composition as claimed in any one of claims 1-14, wherein one dosing unit comprises between 1 and 200 mg carglumic acid, preferably between 1 and 100 mg carglumic acid, most preferably between 25 and 50 mg carglumic acid.

16. Composition as claimed in any one of claims 1-15, wherein one dosing unit comprises 25 or 50 mg carglumic acid.

17. Composition as claimed in any one of claim 1-16, wherein one dosing unit comprises between 1 and 400 mg sodium acetate, preferably between 50 and 200 mg sodium acetate, most preferably between 75 and 150 mg sodium acetate.

18. Composition as claimed in any one of claims 1-17, wherein when the composition is dissolved in a liquid, the resulting solution has a pH between 3.5 and 7.5, preferably between 4.5 and 6.5, more preferably 5.5.

19. Composition as claimed in any one of claims 1-18, wherein the composition is formulated for human subjects.

20. Composition as claimed in claim 19, wherein the human subjects are 0 to 5 years old, preferably 0 to 3 years old.

21. Method for preparing the composition as claimed in any one of the claims 1-19, comprising mixing therapeutically active amounts of carglumic acid and sodium acetate and optionally a pharmaceutically acceptable carrier and / or excipient.

22. Method as claimed in claim 21, wherein sodium acetate is anhydrous sodium acetate.

23. Method as claimed in claim 21 or 22, wherein the pharmaceutically acceptable carrier and / or excipient is a suppository.

24. Method for preventing and / or treating hyperammonaemia, comprising the administration of the composition according to any one of claims 1-20.

25. Method for preventing and / or treating N-acetylglutamate synthase (NAGS) deficiency, comprising the administration of the composition according to any one of claims 1-20.

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