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EP-4734965-A1 - COMPOSITION AND METHOD FOR PRETREATING CANCER

EP4734965A1EP 4734965 A1EP4734965 A1EP 4734965A1EP-4734965-A1

Abstract

The present invention relates to a pharmaceutical composition for oral administration, the pharmaceutical composition comprising a) immediate release granules comprising i. an active ingredient selected from the group consisting of valproic acid, valproate semisodium, sodium valproate and magnesium valproate, and ii. a filler, and b) sustained release pellets comprising: i. pellet cores comprising: (1) an active ingredient selected from the group consisting of valproic acid, valproate semisodium, sodium valproate, and magnesium valproate, and (2) a filler, ii. a subcoat provided on the pellet cores, the content of the subcoat being 10-20 wt% based on the weight of the pellet cores, and the subcoat comprising a film forming agent, and iii. a sustained release coating provided on the subcoat, the content of the sustained release coating being 25-100 wt% based on the weight of the pellet cores coated with the subcoat, and the sustained release coating comprising a film forming agent, wherein the amount of active ingredient in the immediate release granules makes up 70-80 wt% of the total weight of active ingredient in the pharmaceutical composition, and the amount of active ingredient in the sustained release pellets makes up 20-30 wt% of the total weight of active ingredient in the pharmaceutical composition. In further aspects the present invention relates to a method of producing the pharmaceutical composition and the pharmaceutical composition for use in a method of pretreating cancer.

Inventors

  • DROTT, JOHAN
  • NICKLASSON, FREDRIK
  • HORLER, Andrew Nicholas
  • PANCHOLI, Mehul

Assignees

  • Valcuria AB

Dates

Publication Date
20260506
Application Date
20240628

Claims (15)

  1. 1. A pharmaceutical composition for oral administration, the pharmaceutical composition comprising: a) immediate release granules comprising: i. an active ingredient selected from the group consisting of valproic acid, valproate semisodium, sodium valproate, and magnesium valproate, and ii. a filler, b) sustained release pellets, comprising: i. pellet cores comprising: (1) an active ingredient selected from the group consisting of valproic acid, valproate semisodium, sodium valproate, and magnesium valproate, and (2) a filler, ii. a subcoat provided on the pellet cores, the content of the subcoat being 10-20 wt% based on the weight of the pellet cores, and the subcoat comprising a film forming agent, and iii. a sustained release coating provided on the subcoat, the content of the sustained release coating being 25-100 wt% based on the weight of the pellet cores coated with the subcoat, and the sustained release coating comprising a film forming agent, wherein the amount of active ingredient in the immediate release granules makes up 70-80 wt% of the total weight of active ingredient in the pharmaceutical composition, and the amount of active ingredient in the sustained release pellets makes up 20-30 wt% of the total weight of active ingredient in the pharmaceutical composition, and wherein the film forming agent of the sustained release coating is different from the film forming agent of the subcoat.
  2. 2. The pharmaceutical composition according to claim 1, wherein: the amount of active ingredient in the immediate release granules makes up 72-77 wt%, preferably 75 wt%, of the total weight of active ingredient in the pharmaceutical composition, and the amount of active ingredient in the sustained release pellets makes up 23-27 wt%, preferably 25 wt%, of the total weight of active ingredient in the pharmaceutical composition.
  3. 3. The pharmaceutical composition according to any preceding claim, wherein: the content of the active ingredient in the immediate release granules is 75-95 wt%, preferably 77-83 wt%, based on the weight of the immediate release granules, and the content of the active ingredient in the pellet cores is 35-45 wt%, preferably 37-43 wt%, based on the weight of the pellet cores.
  4. 4. The pharmaceutical composition according to any preceding claim, wherein: the content of the subcoat in the sustained release pellets is 14-18 wt%, preferably 15 wt%, based on the weight of the pellet cores.
  5. 5. The pharmaceutical composition according to any preceding claim, wherein: the subcoat comprises, by weight of the subcoat: i. 35-40 wt%, preferably 37.5 wt%, hydroxypropyl cellulose, ii. 35-40 wt%, preferably 37.5 wt%, hydroxypropyl methylcellulose, and iii. 20-30 wt%, preferably 25 wt%, talc
  6. 6. The pharmaceutical composition according to any preceding claim, wherein the sustained release coating comprises, by weight of the sustained release coating: 1) 97-100 wt% film forming agent, and 2) 0-3 wt% of a pore former.
  7. 7. The pharmaceutical composition according to any preceding claim, wherein the content of the sustained release coating in the sustained release pellets is 65-80 wt%, preferably 68-75 wt%, more preferably 70 wt%, based on the weight of the pellet cores provided with the subcoat.
  8. 8. The pharmaceutical composition according to any preceding claim, wherein a) the immediate release granules consist of: i. 90 wt% valproic acid or valproate, ii. 9.5 wt% dicalcium phosphate anhydrous, and iii. 0.5 wt% magnesium stearate, b) the pellet cores consist of: i. 40 wt% valproic acid or valproate, ii. 59 wt% microcrystalline cellulose, and iii. 1 wt% magnesium stearate, c) the subcoat: i. is provided in an amount corresponding to 15 % of the weight of the pellet cores, and ii. comprises, by weight of the subcoat: 1) 37.5 wt% hydroxypropyl cellulose, 2) 37.5 wt% hydroxypropyl methylcellulose, and 3) 25 wt% talc, and d) the sustained release coating: i. is provided in an amount corresponding to 70 % of the weight of the pellet cores coated with the subcoat, and ii. comprises, by weight of the sustained release coating: 1) 98% ethylcellulose, and, 2) 2% of a pore former comprising hydroxypropyl methylcellulose. wherein: the amount of active ingredient in the immediate release granules makes up 75 wt% of the total weight of active ingredient in the pharmaceutical composition, and the amount of active ingredient in the sustained release pellets makes up 25 wt% of the total weight of active ingredient in the pharmaceutical composition.
  9. 9. The pharmaceutical composition according to any preceding claim, further comprising a capsule for holding the immediate release granules and the sustained release pellets, the capsule defining a unit dose of the pharmaceutical composition.
  10. 10. A method of producing the pharmaceutical composition according to any preceding claim, comprising the steps of: i. producing the immediate release granules, ii. producing the pellet cores, iii. coating the pellet cores with the subcoat by performing the substeps of: a. suspending or dissolving the subcoat in aqueous media to form an aqueous solution or dispersion of the subcoat, b. contacting the pellet cores with the aqueous solution or dispersion of the subcoat to produce pellet cores provided with the subcoat, iv. further coating the pellet cores provided with the subcoat with a sustained release coating by performing the substeps of a. suspending or dissolving the sustained release coating in aqueous media to form an aqueous solution or dispersion of the sustained release coating, and b. contacting the pellet cores, coated with the subcoat, with the aqueous solution or dispersion of the sustained release coating to produce sustained release pellets.
  11. 11 . The pharmaceutical composition according to any of the claims 1-10 for use in a method of pretreating cancer, wherein the pharmaceutical composition is administered to a human suffering from cancer.
  12. 12. The pharmaceutical composition for use according to claim 11 , wherein the cancer is selected from the croup consisting of diffuse large B cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukaemia, T cell lymphoma, myeloma, and Hodgkin lymphoma.
  13. 13. The pharmaceutical composition for use according to any of claims 11-12, wherein the pharmaceutical composition is administered prior to the human being treated with chemotherapy and/or immunotherapy.
  14. 14. The pharmaceutical composition for use according to any of claims 11-13, wherein the pharmaceutical composition is administered twice daily.
  15. 15. The pharmaceutical composition for use according to any of claims 11-14, wherein a steroid selected from the group consisting of prednisone, prednisolone, dexamethasone, and betamethasone, is also administered to the human.

Description

COMPOSITION AND METHOD FOR PRETREATING CANCER FIELD OF INVENTION The invention relates to the field of compositions and methods of pretreating cancer, i.e. , where one or more compositions are administered to an individual in need of cancer treatment as a pretreatment prior to other treatments to enhance the effect, or mitigate the side-effects, of the treatments. BACKGROUND OF INVENTION Cancer can be defined as an abnormal growth of cells which exhibits signs of uncontrolled proliferation and disturbed programmed cell death. From a classical view, sequential genetic events lead to malignant transformation, resulting in a cell clone that does not respect the integrity of other cells and tissues, and may eventually metastasize. Cancer can involve any tissue of the body and have many different forms in each body area. Malignant lymphoma can be defined as a malignant transformation of the lymphatic cells of the hematopoietic system. Lymphomas can be divided into aggressive lymphomas and indolent lymphomas. Aggressive lymphomas are characterized by a rapid growth pattern and can have dramatic clinical features. However, aggressive lymphomas can reach a complete cure by treatment with chemotherapy, radiotherapy, and monoclonal antibodies. In contrast, indolent lymphomas (e.g., follicular lymphomas) have a slow growth pattern, and usually a more modest clinical presentation. However, although indolent lymphomas cannot reach a complete cure by standard lymphoma treatment, they can sometimes be cured by allogeneic stem cell transplantation. The median survival time for humans afflicted by follicular lymphomas is 8-10 years. Diffuse Large B Cell Lymphoma and Hodgkin lymphoma belong to the group of aggressive lymphomas, while follicular lymphoma and chronic lymphocytic leukaemia are indolent lymphomas. Myelomas consist of malignantly transformed plasmacells. They are related to indolent lymphomas but are usually considered an entity of their own. The prognosis is pessimistic, with a median survival time of 5-7 years. One of the most frequent subtypes of malignant lymphoma is Diffuse Large B-cell Lymphoma (DLBCL) with an incidence of about 500 cases/year in Sweden. DLBCLs constitute 60-70% of the group of aggressive lymphomas. The median age at diagnosis is 70 years, and DLBCL is slightly more common in males than in females. Standard first line treatment of DLBCL is chemotherapy consisting of a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). During recent years, addition of the CD20 antibody rituximab has become international clinical standard (R-CHOP), leading to improved progression-free, event-free, disease-free and overall survival (Morrison, Expert Rev Anticancer Ther, 2008; 8(10): pp. 1651- 1658). Still, since as many as 45 % of patients die from their disease, there is a pronounced clinical need to increase progression-free survival in DLBCL patients. One important field in the study of cancer diseases is the regulation of DNA transcription. This is a complex process and the mechanisms involved are only partially known. Histone Deacetylases (HDACs) can regulate expression of tumour suppressor genes and activities of transcription factors involved in both cancer initiation and progression. HDACs act through alteration of either DNA or the structural components of chromatin by histone deacetylation, thus affecting the three-dimensional conformation of DNA without changing or interrupting its sequence (epigenetic modifications). It has also been suggested that they may alter the sensitivity to DNA damaging chemotherapy through modulation of chromatin structure. Along these lines, several in vitro studies have suggested that inhibition of HDACs can synergize with chemotherapy. Therefore, numerous HDAC inhibitors have been developed during the recent years. They can be divided into four classes: hydroxamic acids/carbamic acids, cyclic peptides, aliphatic acids and benzamides. Examples of HDAC inhibitors which have been approved for treatment of cancer include vorinostat and romidepsin, which are approved for the treatment of cutaneous T-cell lymphoma by the FDA (Food and drug administration), and which are currently evaluated in the treatment of other malignancies. The clinically most well-known HDAC inhibitor is the anticonvulsant valproic acid, which has been utilized in the treatment of epilepsy since the 1970s. Valproic acid belongs to the aliphatic acid class of inhibitors. The present inventors have previously shown that HDAC inhibitors in combination with steroids are useful when being administered to a human in need of cancer treatment as a pretreatment prior to other treatments, the result being that the effect of the treatment is enhanced, see WO2012/128709. Despite the promise of more effective treatment of cancer made by the advent of pretreatment using a HDAC inhibitor as taught in WO2012/128709, there is still a need for further development. One difficulty that ar