Novel sublingual compositions for the treatment of fibrotic diseases and hypertensive diseases

Abstract

The present invention relates to novel sublingual compositions comprising an anti-fibrotic agent, as well as methods for their preparation. Wherein the composition comprising an anti- fibrotic agent such as pirfenidone or nintedanib and its analogs or pharmaceutically acceptable salts thereof. These novel sublingual compositions are intended for use in the treatment of fibrotic diseases, disorders, or conditions, such as idiopathic pulmonary fibrosis (IPF), and hypertensive diseases, disorders, or conditions such as pulmonary hypertension.

Description

[0001] NOVEL SUBLINGUAL COMPOSITIONS FOR THE TREATMENT OF FIBROTIC DISEASESAND HYPERTENSIVE DISEASES

[0002]

[0001] This application claims the benefit of priority to Indian provisional patent applications number 202441039773 filed dated 21stJuly 2024; 202441039776 filed dated 21stJuly 2024; and 202541026154 filed dated 21stMarch 2025, the disclosures of each of which are incorporated herein by reference in their entirety.

[0003] FIELD OF THE INVENTION

[0004]

[0002] The present invention relates to methods of preparation of novel sublingual formulations or compositions of an anti-fibrotic agents such as pirfenidone, nintedanib, or its analogs, or pharmaceutically acceptable salts thereof, for the treatment of anti -fibrotic diseases, disorders, or conditions such as Idiopathic pulmonary fibrosis (IPF) and hypertensive diseases, disorders, or conditions, such as pulmonary hypertension.

[0005] BACKGROUND OF THE INVENTION

[0006]

[0003] Fibrosis is a progressive condition characterized by excessive accumulation of fibrous connective tissue in the extracellular matrix (ECM) following tissue injury. It affects vital organs like the heart, lungs, liver, kidneys, and skin, leading to high morbidity and mortality. The process is driven by chronic inflammation, TGF-pi signaling, metabolic imbalance, and oxidant-antioxidant disruption. Myofibroblasts play a central role in ECM turnover and collagen (types I and III) production. Pro-fibrotic cytokines, vascular injury, mechanical stress, and ischemia also contribute. Idiopathic Pulmonary Fibrosis (IPF) is a key example of this pathological process.

[0007]

[0004] IPF is the most extensively studied interstitial lung disease (ILD), defined histologically by a usual interstitial pneumonia (UIP) pattern. ILDs differ from obstructive lung diseases like asthma or COPD and involve the lung interstitium.

[0008]

[0005] IPF presents insidiously but rapidly progresses after symptom onset, often resulting in death within 3-5 years. Forced vital capacity (FVC) decline is a strong predictor of mortality, and acute exacerbations carry high fatality. The disease primarily affects males aged 60-65. Its prevalence is estimated at 13.2-20.2 per 100,000.

[0009]

[0006] There is no cure for IPF. Current treatments like pirfenidone and nintedanib offer modest benefits by slowing progression. Management focuses on symptom control and preserving lung function.

[0007] Hypertensive disorders, including essential and secondary hypertension, can lead to organ damage such as heart disease, stroke, and pulmonary hypertension if left uncontrolled.

[0010] Pulmonary Hypertension (PH)

[0011]

[0008] Pulmonary hypertension causes high pulmonary artery pressure from increased resistance, straining the right heart and disrupting normal heart-lung circulation, leading to impaired cardiopulmonary function.

[0012]

[0009] PH is classified into five major groups, as outlined by the World Health Organization (WHO). These groups are based on the underlying causes and pathophysiology of the disease:

[0013] 1. Group 1: Pulmonary Arterial Hypertension (PAH), which includes idiopathic and heritable cases as well as those related to other diseases such as connective tissue diseases or congenital heart defects.

[0014] 2. Group 2: Pulmonary hypertension due to left heart disease.

[0015] 3. Group 3: Pulmonary hypertension due to lung diseases, such as chronic obstructive pulmonary disease (COPD).

[0016] 4. Group 4: Pulmonary hypertension due to chronic thromboembolic disease (CTEPH).

[0017] 5. Group 5: Pulmonary hypertension due to unclear multifactorial mechanisms, such as hematologic disorders or systemic metabolic disorders.

[0018]

[0010] Pulmonary Arterial Hypertension (PAH), classified as Group 1, is the most critical subtype due to its high morbidity and mortality. It involves pulmonary vascular remodeling, leading to increased pulmonary vascular resistance, elevated pressure, and right heart strain, which may eventually progress to right heart failure.

[0019] Pulmonary Arterial Hypertension (PAH)

[0020]

[0011] Pulmonary arterial hypertension (PAH) is a type of pulmonary hypertension with elevated pulmonary artery pressure (>25 mmHg at rest) without identifiable causes like heart or lung disease. Idiopathic PAH has no known cause, while heritable PAH is linked to genetic mutations, especially BMPR2, inherited in an autosomal dominant pattern.

[0021]

[0012] PAH can develop secondary to conditions like connective tissue diseases, congenital heart defects, HIV, or certain drugs (e.g., appetite suppressants). Symptoms are nonspecific, including breathlessness, fatigue, chest pain, and fainting. Disease progression leads to right heart failure and potentially death from sustained cardiac strain. Pathophysiology of PAH

[0022]

[0013] The pathophysiology of PAH is multifactorial and involves several key mechanisms that contribute to vascular remodeling. These mechanisms include endothelial dysfunction, smooth muscle cell proliferation, and fibrosis of the pulmonary vasculature.

[0023] • Endothelial dysfunction in PAH involves increased endothelin-1 (a vasoconstrictor) and reduced nitric oxide and prostacyclin levels, disrupting the vasoconstrictorvasodilator balance and contributing to elevated pulmonary artery pressure.

[0024] • Vascular remodeling causes smooth muscle cell proliferation in pulmonary arterioles, leading to vessel thickening, narrowing, increased resistance, and elevated pulmonary artery pressure.

[0025] • Inflammation has also been implicated in the pathogenesis of PAH. Various inflammatory mediators, such as cytokines and growth factors, have been shown to contribute to vascular remodeling and smooth muscle cell proliferation in PAH (Cao et al., 2013).

[0026] • Genetic mutations, s particularly in the BMPR2 gene, are a key risk factor in familial and some idiopathic PAH cases. These mutations disrupt BMPR2 signaling in the pulmonary vasculature, leading to abnormal vascular remodeling and contributing to the development and progression of pulmonary arterial hypertension (PAH).

[0027] Current Treatment Options for PAH

[0028] While there is no cure for PAH, several treatment options are available to manage the disease. The goals of therapy are to reduce symptoms, improve quality of life, prevent disease progression, and improve survival.

[0029] 1. Vasodilators: Medications such as endothelin receptor antagonists (e.g., bosentan, ambrisentan), phosphodiesterase type 5 inhibitors (e.g., sildenafil), and prostacyclin analogs (e.g., epoprostenol) are commonly used to dilate pulmonary vessels and reduce pulmonary vascular resistance.

[0030] 2. Combination therapy: Recent studies have shown that combination therapy, which targets different pathways involved in PAH pathophysiology, can provide superior outcomes compared to monotherapy (McLaughlin et al., 2014).

[0031] 3. Lung transplantation: In cases of severe PAH unresponsive to medical therapy, lung transplantation may be considered as a life-saving treatment.

[0032]

[0014] Pulmonary Arterial Hypertension (PAH) is a severe vascular disease characterized by elevated pulmonary artery pressure and progressive vascular resistance, often leading to right heart failure and death. Idiopathic (IP AH) and heritable (HP AH) PAH are major subtypes, representing 37%-49% of cases, with a rare incidence of 5-10 per million. These conditions can affect all age groups. Current treatments only provide symptomatic relief through vasodilation but do not reverse the underlying vascular remodeling. This highlights the significant disease burden and the lack of curative therapies. In 2018, the Chinese National Health Commission listed IPAH / HPAH as rare diseases, emphasizing the urgent need for focused research and new, targeted therapeutic strategies.

[0033]

[0015] Idiopathic and heritable pulmonary arterial hypertension (IPAH / HPAH) are autosomal dominant genetic disorders with strong familial patterns. By December 2022, 21 genes had been linked to pulmonary hypertension, with BMP9 and PTGIS first identified by the present inventor’s team. These genes explain 50-70% of HP AH and 20-40% of IP AH cases. Most pathogenic genes, such as BMPR2, ALK1, ENG, CAV1, SOX17, and KDR, are highly expressed in pulmonary endothelial cells, indicating endothelial injury as a key factor. Targeting genes like BMPR2 and SOX17 shows potential in reversing disease mechanisms in animal models, and some approaches are advancing into clinical trials for PAH treatment.

[0034]

[0016] Pulmonary arterial hypertension (PAH) is a rare, progressive, and currently incurable disease, characterized by inflammation and remodeling of distal pulmonary arterioles resulting in increased pulmonary arterial pressure (mPAP) and right ventricular (RV) afterload. This eventually leads to right heart failure and death. _The process of pulmonary vascular remodeling, including neointimal lesions, is orchestrated by endothelial inflammation, changes in the extracellular matrix, and chemoattraction of leukocytes.

[0035]

[0017] Inflammation plays a key role in pulmonary vascular remodeling in PAH, though mechanisms remain unclear. Patients show elevated IL-ip and IL-18 levels, regulated by inflammasomes. Inflammasome activation leads to caspase-1 cleavage, which then processes pro-IL-ip and pro-IL-18 into their active, secreted forms, promoting inflammatory responses.

[0036]

[0018] The NLRP3 inflammasome, comprising NLRP3, ASC, and caspase-1, plays a key role in cardiovascular diseases. Activated by NF-KB priming and caspase-1 triggering, it is expressed in macrophages and endothelial cells. Disturbed blood flow activates it in PAH, and animal studies suggest its role in PH progression, needing further research.

[0037]

[0019] Current treatments have improved survival in PAH patients but remain noncurative, with overall prognosis still poor. No therapy yet reverses the adverse pulmonary vascular remodeling characteristic of PAH. Pirfenidone (5-methyl-l-phenyl-2-[lH]-pyridone, PFD), a synthetic pyridone derivative, possesses antifibrotic, anti-inflammatory, and antioxidative properties and is approved for treating idiopathic pulmonary fibrosis, showing a favorable safety profile. Notably, PFD has demonstrated potential in animal models by suppressing NLRP3 inflammasome activation in pulmonary and cardiac fibrosis, making it a candidate for further exploration in PAH treatment strategies targeting underlying disease mechanisms.

[0038]

[0020] Researchers have investigated whether the NLRP3 inflammasome is activated in a rat model of flow-associated neointimal PAH, induced by monocrotaline (MCT), and aortocaval shunt and whether early PFD treatment affects NLRP3 inflammasome activation, pulmonary hemodynamics, and vascular remodeling.

[0039]

[0021] Despite existing treatments, PAH remains difficult to manage with poor prognosis. Current therapies offer symptomatic relief but fail to target underlying causes like vascular remodeling and endothelial dysfunction. Advancing molecular understanding and developing targeted therapies are crucial for improving outcomes and quality of life in PAH patients.

[0040]

[0022] Pirfenidone, first approved in Japan in 2008, is an orally administered antifibrotic drug used in treating fibrotic diseases. Effective in both animal models and clinical trials, Pirfenidone works by downregulating growth factors and procollagens I and II, and inhibiting TGF-pi -induced fibroblast-to-myofibroblast differentiation. This action reduces collagen production and extracellular matrix buildup, helping to slow fibrosis progression and tissue scarring.

[0041]

[0023] Pirfenidone has a short half-life, requiring multiple daily doses. Common side effects include nausea, fatigue, dizziness, and photosensitive rash, which can affect daily activities and quality of life. These adverse effects are dose-dependent and worsen at higher doses needed to achieve therapeutic levels via oral administration.

[0042]

[0024] As Pirfenidone having very short half-life in humans, it is likely to be dosed at more than once per day. The most common adverse reactions or events associated with Pirfenidone therapy includes gastrointestinal upset, nausea, fatigue, somnolence, dizziness, headache and photosensitive rash. Many of these effects interfere with the day to day activities and effects quality of life. These effects appear to be dose related the adverse reactions associated with Pirfenidone therapy are exacerbated when Pirfenidone is administered at high doses. To achieve the therapeutic dose levels high doses are required by oral route of administration.

[0043]

[0025] Research efforts in the oral drug delivery segment have led to the recent development of oral fast dissolving film / strips. This form of oral mucosal drug delivery is an alternative method of drug delivery that offers several advantages over injectable, inhalable and enteral methods. Because the oral mucosa is highly vascularized, drugs that are absorbed through the oral mucosa directly enter the systemic circulation, by- passing the gastrointestinal tract and first-pass metabolism in the liver.

[0044]

[0026] The oral film / strips offer the advantages of convenience of dosing, portability and wider acceptability by paediatric as well as geriatric population. The advantages of oral films include larger surface area that leads to rapid disintegration and dissolution along with its ease of swallowing property. The oral films aid in quick absorption and instant bioavailability of drugs due to high blood flow and permeability of oral mucosa.

[0045]

[0027] In sublingual administration route, the drug placed under the tongue reaches directly into the blood stream through ventral surface of the tongue and floor of the mouth. Through the reticulated vein which lies underneath the oral mucosa, the drug is rapidly absorbed and transported through the facial, internal jugular and brachiocephalic veins to be drained in to systemic circulation.

[0046]

[0028] The sublingual route usually produces a faster onset of action than orally ingested forms, as the drug is absorbed through the sublingual blood vessels bypassing the hepatic first-pass metabolic processes. The main mechanism for the absorption of the drug in to oral mucosa is via passive diffusion into the lipoidal membrane. For sublingual formulations, the small volume of saliva is usually sufficient for disintegration in the oral cavity. The absorption of the drug through the sublingual route is 3 to 10 times greater than oral route. Peak blood levels of most products administered sublingually are achieved within 10 to 15 minutes, which is generally much faster than when those same drugs are ingested orally. Sublingual absorption is efficient. The percent of each dose absorbed is generally higher than that achieved by means of oral ingestion.

[0047]

[0029] Sublingual drug delivery through the sublingual mucosal membranes covers the ventral side of the tongue and the soft palate. Out of the total surface area of the oral cavity, non-keratinised epithelia involved in the sublingual delivery amounts to 37.32 cm2. In terms of permeability, the sublingual area of the oral cavity is more permeable than the buccal (cheek) area, which in turn is more permeable than the palatal (roof of the mouth) area.

[0048]

[0030] Problem associated with the sublingual tablet formulation is that there is always a risk that the patient will swallow part of the dose before the active substance has been released and absorbed locally into systemic circulation. This could result in an unwanted prolongation of the pharmacological effect. Even the oral spray drug delivery systems have many disadvantages like inaccuracy of dosing, patient incompliance, cost of the preparation and frequency of administration.

[0031] Therefore, the drug of the present invention in preferred low dosage can be delivered in a quick disintegrating sublingual dosage form and, as the disintegration and dissolution of the dosage form occurs rapidly there is rapid onset of action without any lag. The patient can ingest the dosage from anywhere and at any time without the aid of water which would be helpful especially in cases of unavailability of water, motion sickness, sudden episodes of acute exacerbations.

[0049]

[0032] The present invention addresses the disadvantages of state of the art and puts forward the efficiency of the disclosed sublingual films lead to rapid disintegration and dissolution along with its ease of swallowing property. The sublingual films aid in quick absorption and instant bioavailability of drugs due to high blood flow and permeability of oral mucosa.

[0050] OBJECTIVE OF THE INVENTION:

[0051]

[0033] The primary goal of developing a novel drug delivery system for pirfenidone or nintedanib is to enhance its bioavailability while minimizing drug-related toxicity.

[0052]

[0034] This invention focuses on creating a fast-dissolving oral film formulation of pirfenidone or nintedanib that offers improved bioavailability, a rapid onset of action, prolonged therapeutic effect, and reduced dependence on food intake for absorption. It also aims to lower the overall daily dose required and improve patient compliance. Each of these goals is addressed as follows:

[0053] Enhanced Bioavailability and Prolonged Therapeutic Effect:

[0054]

[0035] Advanced formulation strategies are employed to increase the solubility and dissolution rate of pirfenidone or nintedanib, enabling faster and more efficient absorption into the bloodstream.

[0055]

[0036] Incorporation of delivery-enhancing approaches such as solid dispersions, complexation agents, or film-based systems ensures more reliable and sustained drug release. Rapid Onset of Action:

[0056]

[0037] The oral film is designed to disintegrate quickly upon contact with saliva, allowing the drug to be swiftly absorbed through the sublingual and buccal mucosa.

[0057]

[0038] This route bypasses the gastrointestinal tract, offering a faster onset of therapeutic activity than conventional oral dosage forms.

[0058] Avoidance of First-Pass Metabolism:

[0039] By facilitating absorption directly through the oral mucosa, the formulation circumvents hepatic first-pass metabolism, leading to a greater proportion of the active drug reaching systemic circulation.

[0059] Minimized Impact of Fed or Fasted State:

[0060]

[0040] The formulation is optimized to deliver consistent absorption profiles regardless of whether it is taken with or without food, thus ensuring reliable pharmacokinetics and therapeutic outcomes.

[0061] Reduced Dosage Requirements:

[0062]

[0041] With improved bioavailability and targeted mucosal delivery, the effective therapeutic dose of pirfenidone or nintedanib can be substantially reduced.

[0063]

[0042] This minimizes systemic drug exposure, lowering the risk of adverse effects and enhancing overall treatment safety.

[0064] Enhanced Patient Compliance:

[0065]

[0043] The film offers a water-free, easy-to-administer dosage form ideal for patients who have difficulty swallowing pills or require treatment on-the-go.

[0066]

[0044] Pleasant taste and effective taste-masking improve user experience, making adherence to the treatment regimen more likely.

[0067]

[0045] Overall, the invention of a pirfenidone or nintedanib fast-dissolving oral film represents a promising approach to address various challenges associated with conventional oral dosage forms, offering potential benefits in terms of enhanced bioavailability, rapid onset of action, reduced dosing frequency, decreased toxicity, and improved patient compliance.

[0068] SUMMARY OF INVENTION

[0069]

[0046] The present invention provides methods of preparation of a novel sublingual compositions or formulations of an anti -fibrotic agent for the treatment of anti -fibrotic diseases, disorders or conditions or hypertensive diseases, disorders or conditions.

[0070]

[0047] In another embodiment of the present invention provides methods of preparation of a novel sublingual compositions or formulations of an anti-fibrotic agent entrapped niosomes for the treatment of anti-fibrotic diseases, disorders or conditions or hypertensive diseases, disorders or conditions.

[0071]

[0048] The present invention provides methods of preparation of a novel sublingual compositions or formulations of an anti -fibrotic agent for the treatment of anti -fibrotic diseases, disorders or conditions.

[0049] The present invention provides methods of preparation of a novel sublingual compositions or formulations of an anti-fibrotic agent for the treatment of hypertensive diseases, disorders or conditions.

[0072]

[0050] In one embodiment of the present invention, wherein the anti-fibrotic agent of the sublingual compositions or formulations is a TGF-P (Transforming growth factor) inhibitor.

[0073]

[0051] In another preferred embodiment, wherein the anti-fibrotic agent of the sublingual compositions or formulations is pirfenidone or pirfenidone analogues or a tautomer thereof, prodrug thereof, N-oxide thereof, a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0074]

[0052] In another preferred embodiment, wherein the anti-fibrotic agent of the sublingual compositions or formulations is pirfenidone, or pirfenidone analogues or its pharmaceutically acceptable salt thereof.

[0075]

[0053] In another preferred embodiment, wherein the anti-fibrotic agent of the sublingual compositions or formulations is pirfenidone, or its pharmaceutically acceptable salt thereof.

[0076]

[0054] In another preferred embodiment, wherein the anti-fibrotic agent of the sublingual compositions or formulations is Nintedanib or Nintedanib analogues or a tautomer thereof, prodrug thereof, N-oxide thereof, a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0077]

[0055] In another preferred embodiment, wherein the anti-fibrotic agent of the sublingual compositions or formulations is Nintedanib, or Nintedanib analogues or its pharmaceutically acceptable salt thereof.

[0078]

[0056] In another preferred embodiment, wherein the anti-fibrotic agent of the sublingual compositions or formulations is Nintedanib, or its pharmaceutically acceptable salt thereof.

[0079]

[0057] In another embodiment of the present invention, wherein the anti-fibrotic diseases, disorders or conditions is selected from including but not limited to Lung fibrosis or pulmonary fibrosis, liver fibrosis, heart fibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis, Bone marrow fibrosis, kidney fibrosis, skin fibrosis or scleroderma, interstial lung disorders or systemic sclerosis.

[0080]

[0058] In another preferred embodiment of the present invention, the anti-fibrotic diseases, disorders or conditions is Idiopathic pulmonary fibrosis (IPF).

[0081]

[0059] In another embodiment of the present invention, wherein the hypertensive diseases, disorders or conditions is selected from included but not limited to essential hypertension (primary hypertension), secondary hypertension, hypertensive heart disease, hypertensive retinopathy, hypertensive kidney disease (nephrosclerosis), hypertensive cerebrovascular disease, and pulmonary hypertensive diseases.

[0082]

[0060] In another embodiment of the present invention, wherein the hypertensive diseases, disorders or conditions is selected from pulmonary hypertensive diseases.

[0083]

[0061] In another embodiment of the present invention, wherein the hypertensive diseases, disorders or conditions is Pulmonary arterial hypertension (PAH).

[0084]

[0062] In another embodiment of the invention, wherein the present invention provides a method of preparation of sublingual film compositions or formulations an anti-fibrotic agent.

[0085]

[0063] In another embodiment of the invention, wherein the present invention provides a method of preparation of fast dissolving sublingual film compositions or formulations an anti-fibrotic agent.

[0086]

[0064] In another embodiment of the invention, wherein the present invention provides a method of preparation of fast dissolving sublingual film compositions or formulations an anti-fibrotic agent, which can be suitable to dissolve in saliva.

[0087]

[0065] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises an anti-fibrotic agent, and pharmaceutically acceptable excipients.

[0088]

[0066] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises pirfenidone, or pirfenidone analogues or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.

[0089]

[0067] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises nintedanib, or nintedanib analogues or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.

[0090]

[0068] In another embodiment, the pharmaceutically acceptable excipients may include, but not limited to one or more of the following: a Film forming polymer, a plasticizer, a Buffering agent, a Binder, Acidifier, a Saliva stimulating agent, a Sweetener, a Flavouring agent, a Colouring agent and / or a solvent.

[0091]

[0069] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises pirfenidone, or pirfenidone analogues or its pharmaceutically acceptable salt thereof and one or more excipients selected from the following a Film forming polymer, a plasticizer, a Buffering agent, a Binder, an Acidifier, a Saliva stimulating agent, a Sweetener, a Flavouring agent, a Colouring agent and / or a solvent.

[0070] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises nintedanib, or nintedanib analogues or its pharmaceutically acceptable salt thereof and one or more excipients selected from the following a Film forming polymer, a plasticizer, a Buffering agent, a Binder, an Acidifier, a Saliva stimulating agent, a Sweetener, a Flavouring agent, a Colouring agent and / or a solvent.

[0092]

[0071] In another embodiment, the pharmaceutically acceptable excipients may include, but not limited to one or more of the following: a Film forming polymer or film former, a plasticizer, a buffering agent, a binder, an acidifier, a Sweetener, a Saliva stimulating agent, a Flavouring agent, a Colouring agent, a process excipient or a stabilizer, a preservative and / or a solvent.

[0093]

[0072] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises pirfenidone, or pirfenidone analogues or its pharmaceutically acceptable salt thereof and may include, but not limited to one or more of the following pharmaceutically acceptable excipients selected from at least a Film forming polymer or a or film former, a plasticizer, a buffering agent, a binder, a acidifier, a Sweetener, a Saliva stimulating agent, a Flavouring agent, a Colouring agent, a process excipient or a stabilizer, a preservative and / or a solvent.

[0094]

[0073] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises nintedanib, or nintedanib analogues or its pharmaceutically acceptable salt thereof and may include, but not limited to one or more of the following pharmaceutically acceptable excipients selected from at least a Film forming polymer or a or film former, a plasticizer, a buffering agent, a binder, a acidifier, a Sweetener, a Saliva stimulating agent, a Flavouring agent, a Colouring agent, a process excipient or a stabilizer, a preservative and / or a solvent.

[0095]

[0074] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 1% to about 80% (w / w) of an anti -fibrotic agent.

[0096]

[0075] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 1% to about 80% (w / w) of pirfenidone, or pirfenidone analogues or its pharmaceutically acceptable salt thereof.

[0097]

[0076] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 10% to about 75% (w / w) of pirfenidone, or pirfenidone analogues or its pharmaceutically acceptable salt thereof.

[0077] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 15% to about 75% (w / w) of pirfenidone, or pirfenidone analogues or its pharmaceutically acceptable salt thereof.

[0098]

[0078] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 1% to about 80% (w / w) of pirfenidone, or its pharmaceutically acceptable salt thereof.

[0099]

[0079] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 10% to about 75% (w / w) of pirfenidone, or its pharmaceutically acceptable salt thereof.

[0100]

[0080] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 15% to about 75% (w / w) of pirfenidone, or its pharmaceutically acceptable salt thereof.

[0101]

[0081] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 5%, 10%, 15%, 20, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% (w / w) of pirfenidone, or its pharmaceutically acceptable salt thereof.

[0102]

[0082] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 1% to about 80% (w / w) of nintedanib, or its pharmaceutically acceptable salt thereof.

[0103]

[0083] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 10% to about 75% (w / w) of nintedanib, or its pharmaceutically acceptable salt thereof.

[0104]

[0084] In another embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 15% to about 75% (w / w) of nintedanib, or its pharmaceutically acceptable salt thereof.

[0105]

[0085] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 5%, 10%, 15%, 20, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% (w / w) of nintedanib, or its pharmaceutically acceptable salt thereof.

[0106]

[0086] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 5% to about 50% (w / w) of film forming polymer, about 0% to about 20% (w / w) of a plasticizer, about 0% to about 20% (w / w) of a buffering agent, about 0% to about 20% (w / w) of a binder, about 0% to about 20% (w / w) of acidifier, about 0% to about 6% (w / w) of a saliva stimulating agent, about 3% to about 35% (w / w) of a Sweetener, about 0% to about 10% (w / w)of a flavouring agent and about 0% to about 1% (w / w) of a colouring agent.

[0107]

[0087] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 5% to about 50% (w / w) of a film forming polymer.

[0108]

[0088] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 8% to about 50% (w / w) of a film forming polymer.

[0109]

[0089] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 0% to about 20% (w / w) of a plasticizer.

[0110]

[0090] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 0% to about 20% (w / w) of a buffering agent.

[0111]

[0091] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 0% to about 20% (w / w) of a binder.

[0112]

[0092] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 1% to about 8% (w / w) of a binder.

[0113]

[0093] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 0% to about 20% (w / w) of an acidifier.

[0114]

[0094] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 1% to about 9% (w / w) of an acidifier.

[0115]

[0095] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 0% to about 6% (w / w) of a saliva stimulating agent.

[0116]

[0096] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 3% to about 35% (w / w) of a sweetener agent.

[0097] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 5% to about 32% (w / w) of a sweetener agent.

[0117]

[0098] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 7% to about 31% (w / w) of a sweetener agent.

[0118]

[0099] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 0% to about 10% (w / w) of a flavouring agent.

[0119]

[0100] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 0.01% to about 1% (w / w) of a flavouring agent.

[0120]

[0101] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 0.01% to about 0.1% (w / w) of a flavouring agent.

[0121]

[0102] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 0% to about 1% (w / w) of a colouring agent.

[0122]

[0103] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises about 0.01% to about 0.1% (w / w) of a colouring agent.

[0123]

[0104] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises a process excipient or a stabilizer in a suitable range.

[0124]

[0105] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises a preservative such as an antioxidant in suitable range.

[0125]

[0106] In another preferred embodiment of the invention, the sublingual film composition or formulation of the present invention comprises a solvent in a suitable range.

[0126]

[0107] In another embodiment of the invention, the present invention is related to the method of preparation of a sublingual film composition comprising of an anti -fibrotic agent and pharmaceutically acceptable excipients for the treatment of anti -fibrotic diseases, disorders or conditions or hypertensive diseases, disorders or conditions.

[0108] In another embodiment of the invention, the present invention is related to the method of preparation of a sublingual film composition comprising of pirfenidone or pirfenidone analogues and pharmaceutically acceptable excipients for the treatment of anti- fibrotic diseases, disorders or conditions or hypertensive diseases, disorders or conditions.

[0127]

[0109] In another embodiment of the invention, the present invention is related to the method of preparation of a sublingual film composition comprising of nintedanib or nintedanib analogues and pharmaceutically acceptable excipients for the treatment of anti -fibrotic diseases, disorders or conditions or hypertensive diseases, disorders or conditions.

[0128] [HO] In another embodiment of the invention, the present invention is related to the method of preparation of a fast-dissolving oral film composition comprising of an anti-fibrotic agent and pharmaceutically acceptable excipients for the treatment of anti-fibrotic diseases, disorders or conditions or hypertensive diseases, disorders or conditions.

[0129] [Hl] In another embodiment of the invention, the present invention is related to the method of preparation of a fast-dissolving oral film composition comprising of pirfenidone or pirfenidone analogues and pharmaceutically acceptable excipients for the treatment of anti- fibrotic diseases, disorders or conditions or hypertensive diseases, disorders or conditions.

[0130]

[0112] In another embodiment of the invention, the present invention is related to the method of preparation of a fast-dissolving oral film composition comprising of nintedanib or nintedanib analogues and pharmaceutically acceptable excipients for the treatment of anti- fibrotic diseases, disorders or conditions or hypertensive diseases, disorders or conditions.

[0131] BRIEF DESCRIPTION OF THE DRAWINGS

[0132]

[0113] Figure 1: images depicting the disintegration time of sublingual film under simulated physiological conditions

[0133]

[0114] Figure 2: line graph depicting the Comparative Pharmacokinetics to evaluate bioavailability of drug solution through oral and sublingual routes in male New Zealand rabbits.

[0134]

[0115] Figure 3: image shows the safety evaluation of photosensitivity reduction with sublingual versus oral pirfenidone in male mice.

[0135] DETAILED DESCRIPTION OF THE INVENTION

[0136] Definitions:

[0137]

[0116] The terms "treat," "treating" or "treatment," as used herein, include alleviating, abating or ameliorating a disease, disorder or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease, disorder or condition, e.g., arresting the development of the disease, disorder or condition, relieving the disease, disorder or condition, causing regression of the disease, disorder or condition, relieving a condition caused by the disease, disorder or condition, or stopping the symptoms of the disease, disorder or condition either prophylactically and / or therapeutically.

[0138]

[0117] The terms “Inhibition” “inhibits” and “inhibitor” refer to a compound that partially or completely blocks or prohibits or a method of partially or fully blocking or prohibiting, a specific action or function. The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0139]

[0118] By "pharmaceutically acceptable," as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0140]

[0119] Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, tri -alkylamine, thiamine, and the like; chiral bases like alkylphenylamine, glycinol, and phenyl glycinol, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine; quaternary ammonium salts of the compounds of invention with alkyl halides, and alkyl sulphates such as Mel and (Me)2SO4, non-natural amino acids such as D-isomers or substituted amino acids; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts and aluminium salts. Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates. Pharmaceutically acceptable solvates may be hydrates or comprise other solvents of crystallization such as alcohols.

[0141]

[0120] The term "pharmaceutical composition" refers to a mixture of a compound of the present invention with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients.

[0121] A "fibrotic condition," "fibroproliferative condition," "fibrotic disease," "fibroproliferative disease," "fibrotic disorder," and "fibroproliferative disorder" are used interchangeably to refer to a condition, disease or disorder that is characterized by dysregulated proliferation or activity of fibroblasts and / or abnormal accumulation of fibronectin and / or pathologic or excessive accumulation of collagenous tissue. Typically, any such disease, disorder or condition is amenable to treatment by administration of a compound having anti- fibrotic activity. Fibrotic disorders include, but are not limited to, pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis from a known etiology, dermal fibrosis, pancreatic fibrosis, liver fibrosis (e.g., hepatic fibrosis associated with chronic active hepatitis), and renal fibrosis.

[0142]

[0122] “Hypertension” as referred to herein, and which may also be referred to as “high blood pressure”, is a long-term medical condition characterized by persistently high blood pressure in the arteries. Long-term complications from high blood pressure include coronary artery disease, stroke, heart failure, atrial fibrillation, peripheral arterial disease, chronic kidney disease, dementia, retinopathy and loss of vision. According to WHO, hypertension is diagnosed if, when it is measured on two different days in an adult (i.e. a human subject 18 years or older), the systolic blood pressure readings on both days is3140 mmHg and / or the diastolic blood pressure readings on both days is390 mmHg. Hypertension is further defined, for example, in “2018 ESCZESH Guidelines for the management of arterial hypertension” (European Heart Journal, 39 (33): 3021-3104, 1 September 2018), the content of which is incorporated herein by reference.

[0143]

[0123] The terms "therapeutically effective amount," as used herein, refer to an amount of a compound sufficient to cure, ameliorate, slow progression of, prevent, or reduce the likelihood of onset of the identified disease or condition, or to exhibit a detectable therapeutic, prophylactic, or inhibitory effect. The effect can be detected by, for example, the assays disclosed in the following examples. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically and prophylactically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0144]

[0124] A particular embodiment of the invention incorporates a “plasticizer” to impart flexibility, enhance elasticity and decrease brittleness. Preferred plasticizers include but not limited to triacetine, citrate derivatives (such as triethyl, tributyl, acetyl tributyl, acetyl triethyl, trioctyl, acetyl trioctyl, trihexyl citrate, etc.), dibutyl sebacate, glycerol, polyethylene glycol, propylene glycol or combinations thereof. In accordance with the present invention plasticizer desirably ranges about 0% to 20% w / w of the total sublingual film, preferably about 2% to 15% w / w of the total sublingual film and more preferably about 3% to 12% w / w of the total sublingual film.

[0145]

[0125] One or more pharmaceutically acceptable pH adjusting agents and / or “buffering agents” can be included in a composition of the invention, including but not limited to acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxy methyl aminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition.

[0146]

[0126] “Film-forming agents” used alone or in combination in the compositions of the present invention include, but are not limited to hydroxypropyl methylcellulose grades, hydroxy propyl cellulose, Sodium carboxy methyl cellulose, polyvinyl alcohol, polyvinyl acetate, hydroxyethyl cellulose (HEC), methylcellulose (MC), ethyl cellulose (EC), polyvinyl pyrrolidone (copovidone), poly-ethylene oxide, carrageenan, gelatin, dextrin, polyethylene oxide, Starch, Pectin, Sodium alginate, guar gum, xanthan gum, carrageenan, Glycerol monooleate, maltodextrin, Tragacanth gum, sodium citrate dihydrate, polyvinyl alcoholpolyethylene glycol co-polymers, carboxylic acid containing polymers such as acrylic acid, methacrylic acid, esterified poly acrylic acid polymers, such as polyacrylic acid polymers lightly crosslinked with a poly-alkenyl polyethers; methacrylate polymers; maleic acid copolymers; methacrylic acid-ethyl acrylate copolymers, methacrylic acid and methacrylate based polymers, and a methyl methacrylate copolymer. Preferably used Film-forming agents include polyvinyl alcohol, hydroxypropyl methylcellulose, maltodextrin, HPMC grades like Methocel E50 and Methocel E5, polyethylene oxide or combinations thereof.

[0147]

[0127] Sweeteners used alone or in combination in the compositions of the present invention include, but are not limited to natural and artificial sweeteners. Non-limiting examples of suitable sweeteners include, e.g: water-soluble sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (laevulose), sucrose (sugar), high fructose corn syrup, maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolysed starch, com syrup solids, and dihydrochalcones; water-soluble artificial sweeteners such as the soluble saccharin salts, i.e., sodium or calcium saccharin salts, cyclamate salts, the sodium, ammonium or calcium salt of 3,4-dihydro-6-methyl-l, 2, 3-oxathiazine-4-one-2, 2- dioxide, the potassium salt of 3,4-dihydro-6-methyl-l, 2, 3-oxathiazine-4-one-2, 2-dioxide (acesulfame-K), the free acid form of saccharin and the like; dipeptide based sweeteners, such as L-aspartic acid derived sweeteners, such as L-aspartyl-L-phenylalanine methyl ester (aspartame), L-alpha-aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide hydrate, methyl esters of L-aspartyl-L-phenyl glycerin and L-aspartyl-L-2, 5, dihydrophenylglycine, L- aspartyl-2,5-dihydro-L-phenylalanine, L-aspartyl-L-(l-cyclohexyen)-alanine, and the like; water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, such as a chlorinated derivatives of ordinary sugar (sucrose), known, for example, as sucralose; and protein based sweeteners such as thoracoccus danielli (Thaurnatin I and II), naturally occurring high intensity sweeteners, such as Lo Han Kuo, stevia, steviosides, monellin, Neotame, Alitame, Sucrose, Fructose, Sorbitol, Mannitol, Aspartame, Saccharin Sodium, Glucose, Dextrose, Isomaltose, Acesulfame Potassium, Sorbitol, Ribose, Mannose, Galactose, Maltose, Partially Hydrolysed Starch, Com Syrup, Xylitol, Mannitol, Saccharin Salts, Cyclamate Salts, Thaurnatin I & II, Natural and Artificial bitter masker, Advantame, Tagatose, Stevia, glycyrrhizin, sodium cyclamate and honey. Preferably used sweeteners include acesulfame potassium, aspartame and sorbitol or combinations thereof.

[0148]

[0128] The term “binders” are essential excipients used to hold powdered ingredients together in solid dosage forms like tablets and granules. They act as adhesives, ensuring the tablet's integrity and uniformity. By binding particles, binders improve tablet strength, disintegration properties, and dose accuracy. Natural binders are Starches (like corn starch, potato starch), gums (like acacia, guar gum), and cellulose derivatives (like HPMC). Synthetic binders are Polyvinylpyrrolidone (PVP), polyethylene glycol (PEG)

[0149]

[0129] The term “acidifiers” are the substances that lower the pH of a solution, making it more acidic. They are used to enhance the stability of active compounds, improve drug solubility, and control pH in various formulations. Acidifiers can also be employed to increase the acidity of the stomach (gastric acidifiers) or urine (urinary acidifiers). Dilute hydrochloric acid (HC1), organic acids like citric acid, fumaric acid, and lactic acid etc., are some of the widely used acidifiers.

[0150]

[0130] The pharmaceutical sublingual film incorporates at least one “surfactant / non- ionic solubilizer” chosen from the following but not limited to poloxamer, poly oxyl- hydrogenated castor oil, glyceryl polyethylene glycol oxy-stearates, fatty acid glyceryl poly glyceryl esters, poly glyceryl esters, and combinations thereof.

[0151]

[0131] The pharmaceutical sublingual film incorporates at least one “colouring agent”, which may be provided in a dosage form of the present invention, including but non-limiting pharmaceutically acceptable natural or artificially synthesized dyes. A great variety of such pharmaceutically acceptable dyes have been known to be suitable for use in pharmaceutical compositions, for example natural dyes such as annatto extract, anthocyanins, beta-carotene, beta APO 8, carotenal, black currant, burnt sugar, canthaxanthin, caramel, carbo medicinalis, carmine, carmine blue, carminic acid, carrot, chlorophyll, chlorophyllin, cochineal extract, copper-chlorophyll, copper-chlorophyllin, curcumin, curcumin / CU-chloro, elderberry, grape, hibiscus, lutein, mixed carotenoids, paprika, riboflavin, titanium dioxide, turmeric, natural colours, aronia / red fruit, beet juice colours, paprika extract, paprika oleoresin; or artificial dyes such as allura red, brilliant blue FCF, amaranth, carmoisine, fast red E, erythrosine, green S, patent blue V, ponceau 4R, quinoline yellow, red 2G, sunset yellow, FD&C yellow and tartrazine.

[0152]

[0132] The present formulation may also include one or more “saliva stimulating agents” such as a food acid, e.g. citric, lactic, malic, succinic, ascorbic, adipic, fumaric or tartaric acid, or mixtures thereof. Preferred food acids are citric, malic and ascorbic acids. The amount of saliva stimulating agent suitable for inclusion in the present formulation may range from about 0.01 to about 12 wt. %, preferably about 1 wt. % to about 10 wt. %, more preferably about 2 wt. % to about 6 wt. %

[0153]

[0133] “Flavouring agents” used alone or in combination in the compositions of the present invention include, but are not limited to natural and artificial flavours. These flavourings may be chosen from synthetic flavour oils and flavouring aromatics, and / or oils, oleo resins and extracts derived from plants, leaves, flowers, fruits and so forth, and combinations thereof. Non-limiting flavour oils include: spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, and oil of bitter almonds. Also useful are artificial, natural or synthetic fruit flavours such as vanilla, chocolate, coffee, cocoa and citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and the like. These flavourings can be used individually or in combination. Commonly used flavours include mints such as peppermint, artificial vanilla, cinnamon derivatives, and various fruit flavours, whether employed individually or in combination. Flavourings such as aldehydes and esters including cinnamyl-acetate, cinnamaldehyde, citral, diethyl-acetal, dihydro-carvyl acetate, eugenyl-formate, p-methyl anisole, and the like may also be used. Further examples of aldehyde flavourings include, but are not limited to acetaldehyde (apple); benzaldehyde (cherry, almond); cinnamaldehyde (cinnamon); citral, i.e., alpha citral (lemon, lime); neral, i.e. beta citral (lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla, cream); helio tropine, i.e., piperonal (vanilla, cream); vanillin (vanilla, cream); alpha- amyl cinnamaldehyde (spicy fruity flavours); butyraldehyde (butter, cheese); valeraldehyde (butter, cheese); citronellal (modifies, many types); decanal (citrus fruits); aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus fruits); aldehyde C-12 (citrus fruits); 2-ethyl butyraldehyde (berry fruits); hexenal, i.e. trans-2 (berry fruits); tolyl aldehyde (cherry, almond); veratraldehyde (vanilla); 12,6-dimethyl-5-heptenal, i.e. melonal (melon); 2 dimethyl -octanal (greenfruit); and 2- dodecenal (citrus, mandarin); cherry; anis flavour; grape; mixtures thereof; and the like. Preferably used flavouring agents include cherry flavour, anis flavour, peppermint flavour and lemon mint flavour.

[0154]

[0134] Stabilizers” or “Stabilizing agents” (also called absorption enhancers) may be used, e.g., to inhibit or retard drug decomposition reactions that include, by way of example, oxidative reactions. Stabilizing agents include but not limited to d-Alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), acacia, albumin, alginic acid, aluminium stearate, ammonium alginate, ascorbic acid, ascorbyl palmitate, bentonite, butylated hydroxytoluene, calcium alginate, calcium stearate, calcium carboxymethylcellulose, carrageenan, ceratonia, colloidal silicon dioxide, cyclodextrins, diethanol-amine, edetates, ethylcellulose, ethyleneglycol palmitostearate, glycerin monostearate, guar gum, hydroxypropyl cellulose, hypromellose, invert sugar, lecithin, magnesium aluminium silicate, monoethanol -amine, pectin, poloxamer, polyvinyl alcohol, potassium alginate, potassium polacrilin, povidone, propyl gallate, propylene glycol, propylene glycol alginate, raffmose, sodium acetate, sodium alginate, sodium borate, sodium carboxymethyl cellulose, sodium stearyl fumarate, sorbitol, stearyl alcohol, sufobutyl-b-cyclodextrin, trehalose, white wax, xanthan gum, xylitol, yellow wax, and zinc acetate. In certain embodiments, the stabilizer is, relative to the drug core, present in the amount of about 1% w / w of the drug core, about 2% w / w of the drug core, about 3% w / w of the drug core, about 4% w / w of the drug core, about 5% w / w of the drug core, about 6% w / w of the drug core, about 7% w / w of the drug core, about 8% w / w of the drug core, about 9% w / w of the drug core, about 10% w / w of the drug core, about 12% w / w of the drug core, about 14% w / w of the drug core, about 16% w / w of the drug core, about 18% w / w of the drug core, about 20% w / w of the drug core, about 22% w / w of the drug core, about 24% w / w of the drug core, about 26% w / w of the drug core, about 28% w / w of the drug core, about 30% w / w of the drug core, about 32% w / w of the drug core, between about 1% and about 10% w / w of the drug core, between about 2% and about 8% w / w of the drug core, between about 3% and about 7% w / w of the drug core, or between about 4% and about 6% w / w of the drug core. In certain embodiments, a suitable amount of a particular stabilizer is determined by one of ordinary skill in the art.

[0155]

[0135] “Antimicrobial agents” or “preservatives” include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chloro-butanol, methyl and propyl p- hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anaesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethyl celluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, including poly-oxyethylene sorbitan monolaurate, poly-oxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including a-cyclodextrin, P-cyclodextrin, hydroxypropyl-P- cyclodextrin, sulfobutylether-P-cyclodextrin, and sulfobutylether 7-P-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

[0156]

[0136] The compositions of the present invention are prepared by using following methods:

[0157]

[0137] Solvent-casting method: In the solvent-casting method, water-soluble ingredients are dissolved to form a viscous solution, combined with the active pharmaceutical ingredient, and cast into films which are then dried and cut into desired sizes.

[0158]

[0138] Semi-solid casting method: Semi-solid casting involves preparing a solution of water-soluble film-forming polymer, adding it to an insoluble polymer prepared in a base solution, adding plasticizer to form a gel mass, and casting it into films using heat-controlled drums.

[0159]

[0139] Extrusion (hot-melt and solid dispersion) method: Hot-melt extrusion shapes a polymer into a film by heating, where the drug carrier mix is conveyed, mixed, and melted before being shaped into the desired film form. Solid-dispersion extrusion dissolves the drug in a suitable solvent, incorporates it into a melt of PEG, and forms a solid dispersion.

[0160]

[0140] Rolling method: Rolling method involves preparing a premix of film-forming polymer, polar solvent, and other ingredients, adding the active pharmaceutical ingredient, blending to form a homogenized matrix, and then forming the film on a substrate and drying it.

[0161]

[0141] The composition of the present invention can be prepared by using following methods:

[0162] General Composition 1:

[0163]

[0142] General Composition for the formulation of the present invention:

[0164] Table-1

[0165] General Composition 2:

[0166]

[0143] General Composition for the formulation of the present invention:

[0167] Table-2

[0168] General Composition 3:

[0169]

[0144] General Composition for the formulation of the present invention:

[0170] Table-3

[0171] General Composition 4:

[0172]

[0145] Another General Composition for the formulation of the present invention:

[0173] Table-4

[0174] General Composition 5:

[0175]

[0146] General Composition for the formulation of the present invention:

[0176] Table-5

[0177] General Composition 6:

[0178]

[0147] General Composition for the formulation of the present invention:

[0179] Table-6

[0180]

[0148] General Procedure for preparation of sublingual film-1:

[0181] Following steps can be followed for the preparation of sublingual film of an anti-fibrotic agent: a. Dispense aqueous phase ingredients into mixing vessel under inert conditions. b. Begin low-speed mixing to ensure initial dispersion. c. Gradually ramp up mixing to moderate speed. d. Incorporate binder under controlled mixing and vacuum. e. Maintain nitrogen overlay to prevent oxidation. f. Continue mixing until clear and homogenous solution is achieved. g. Pre-weigh film formers and flavoring agent separately. h. Add initial portion of dry excipients under controlled mixing. i. Complete dry powder addition and continue mixing at higher speed. j . Ensure blend is processed under temperature-controlled conditions. k. Dissolve API (i.e. an anti-fibrotic agent such as pirfenidone or nintedanib) in pharmaceutical solvent to form a clear solution. l. Introduce drug solution into main blend while mixing. m. Continue mixing to ensure complete drug incorporation. n. Final homogenization under optimized mixing speed. o. Collect composite sample for quality evaluation. p. Cast and dry the film using standard film-coating equipment under controlled conditions and q. Monitor critical process parameters throughout coating and drying stages.

[0182]

[0149] General Procedure for preparation of sublingual film-2:

[0183] 1.1. Charge the blending vessel with the formulation amounts of Non-Sterile Purified Water, Citric Acid Anhydrous, Maltitol, sucralose, FD&C Blue. Seal the vessel and add Nitrogen, NF gas overlay to the vessel

[0184] 1.2. Start mixing of vessel the forward direction at 100±10 rpm. Mix for no less than 10 minutes and continue mixing through the next step.

[0185] 1.3. Increase the mixer speed to 200±10 rpm and mix in the forward direction.

[0186] 1.4. Weigh the formulation amount of Povidone K-30 USP and add in to the Vessel through bottom valve using vacuum while mixing.

[0187] 1.5. Seal the vessel and add Nitrogen gas overlay to the vessel up to a max of 1 psi.

[0188] 1.6. After adding Povidone K-30, mix for minimum of 60 minutes till all powder is dissolved.

[0189] 1.7. In separate stainless steel dispenser Polyethylene Oxide, NF (N10 Grade), Polyethylene Oxide, NF (N80 Grade), of Polyethylene Oxide, NF (1105 Grade), Orange flavor.

[0190] 1.8. While mixing, add approximately half of the powders in the stainless steel pail(s) to the Vessel through bottom valve using vacuum.

[0191] 1.9. Once approximately half the powder has been added, the mixer should be stopped momentarily to allow for entrapped air to escape and the mixer speed should be increased to 350 ± 10 rpm and re-start mixing in the forward direction. 1.10. While mixing, add the second portion of the powders weighed in the stainless steel pail(s) to the vessel.

[0192] 1.11. Once added, the mixer should be stopped momentarily to allow for entrapped air to escape. The mixer speed should be increased to 400 ±10 rpm and re-start mixing in the forward direction.

[0193] 1.12. Blend temperature should be maintained at NMT 100.0 °F.

[0194] 1.13. Weigh an anti-fibrotic agent such as pirfenidone or nintedanib and Ethyl Alcohol in Jar and Seal the jar and mix on the jar rotator at speed setting 5. Mix for a minimum of 20 minutes and continue mixing until all of the powder is dissolved.

[0195] 1.14. Once the powder in the jar is dissolved, release the nitrogen overlay and add the contents of the jar to the mixing vessel through a port using a funnel.

[0196] 1.15. After addition, mix the vessel for minimum of 180 minutes.

[0197] 1.16. The mixer is stopped momentarily to allow for entrapped air to escape. The mixer speed should be increased to 425 ± 10 rpm and re-start mixing in the forward direction and mix minimum for 60 minutes.

[0198] 1.17. After blending, sample the blend from top, middle, bottom and composite and submit samples to lab.

[0199]

[0150] Coating & drying:

[0200] 1.18. Polymeric drug dispersion of step 1.16 was transferred to coating trough by using peristaltic pump

[0201] 1.19. Then coated on a polyester sheet using Dr. knife separator and dried in hot air oven chambers by using below mentioned parameters

[0202] Table-7

[0203] 1.20. After performing trial coat with the above process parameters if target weight of film is achieved then same parameters shall be used till completion of process, otherwise parameters can be adjusted as per requirement in order to get the film with desired weight.

[0204] Table-8

[0205] 1.21. If all the process parameters are within the In-process limits, start the final coating and drying. Perform the In-process checks at initial and after every two hours and record them. Monitor all process parameters continuously throughout coating and drying process.

[0206] 1.22. While performing coating & drying operation ensure that temperature and RH of the area should be maintained at 20 to 25°C & 40 to 50 % respectively.

[0207]

[0151] Slitting:

[0208] 1.23. Transfer the mother roll into slitting area.

[0209] 1.24. Slit the mother roll into small rolls by using slitting machine.

[0210] 1.25. Slitted roll Width should be 28 mm ± 1 mm (W).

[0211] 1.26. Slitted roll will be sent to packing area.

[0212] 1.27. While performing slitting operation ensure that temperature and RH of the area should be maintained at 20 to 25°C & 40 to 50 % respectively.

[0213]

[0152] CUTTING & PACKAGING

[0214] 1.28. Pack the approved Pirfenidone Sublingual Films as per current approved Packaging order / packaging instruct! ons / Bill of packaging material. 1.29. Slitted roll to be cut into different size and peeled off from the polyester sheet and packed into pouches.

[0215] 1.30. Final film shall be packed and sealed by using automatic packing machine.

[0216] 1.31. Check the sealing of pouch physically.

[0217] 1.32. Pack required number pouches in a carton.

[0218] 1.33. If required, pack cartons into shipper box.

[0219] 1.34. While performing packing operation ensure that temperature and RH of the area should be maintained at 20 to 250C & 40 to 50 % respectively

[0220] Example-1

[0221] Compositions (lOmg film):

[0222] Table-9 Example-2

[0223] Compositions (25mg film):

[0224] Table-10

[0225] Example-3

[0226] Compositions (50mg film):

[0227] Table-11

[0228] Example-4

[0229] Compositions (lOOmg film):

[0230] Table-12

[0231] Example-5

[0232] Compositions (200mg film):

[0233] Table-13

[0234] Stability Data:

[0235]

[0153] Table 7 includes stability data for the sublingual film of the present invention. The sublingual Pirfenidone film of the present invention was stored at 40°C±2° / 75±5% RH and assay and impurities were measured for six months. As can be seen from the results, the sublingual film of the present invention remains more than 95% of Pirfenidone, and total impurities were less than 1 %.

[0154] Stability data and impurities data: Pirfenidone assay (by HPLC, w / w) provided below in Table-7:

[0236] Table-14

[0237] NMT=Not More Than; M=month

[0238] RABBIT PHARMACOKINETICS DATA:

[0239] STUDY PROTOCOL:

[0240]

[0155] Pirfenidone was dissolved in sterile water to achieve a concentration of 1 mg / mL. Test animals (New Zealand White rabbits) were divided into two groups, with each group consisting of three animals. Group 1 received the test formulation via the oral route, while Group 2 received the test formulation via the sublingual route.

[0241]

[0156] Blood samples were collected from each animal at nine time points: pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 7 hours, and 24 hours postadministration. Plasma was separated from the collected blood samples, and pharmacokinetic parameters were calculated based on the plasma concentrations. The resulting data are presented in Table 15 below.

[0242] Table-15 In Vivo phototoxicity evaluation assay:

[0243] Comparative In Vivo phototoxicity evaluation of Pirfenidone administered via oral and sublingual routes in BALB / c male mice following repeated dosing and UV Exposure.

[0244]

[0157] Pirfenidone was dissolved in sterile water at Img / ml strength. Pirfenidone sublingual films were prepared with pirfenidone 3mg per film.

[0245]

[0158] Experimental procedures: Male BALB / c mice (6-8 weeks old, 20-25 g) were randomly divided into two groups (n=6 / group) and administered Pirfenidone at a dose of 100 mg / kg body weight once daily for 21 consecutive days via either oral gavage (Group 1) or sublingual film application (Group 2). Control animals (n=3 / group) received the respective vehicle formulations. On Day 22, mice were anesthetized, and a 2^2 cm area of dorsal skin was shaved and exposed to a calibrated dose of ultraviolet (UV) light (5 J / cm2UVA + 0.5 J / cm2UVB) using a solar simulator, while eyes were protected. Post-UV exposure, animals were observed for 72 hours for clinical signs of phototoxicity including erythema, edema, rash, and scaling. Skin reactions were graded using a semi-quantitative scoring system adapted from the Draize scale. At the end of the observation period, animals were euthanized, and skin samples were collected for histopathological examination. The severity of dermal lesions was compared between oral and sublingual groups to assess the route-dependent phototoxic potential of Pirfenidone.

[0246]

[0159] The present invention has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed.

[0247]

[0160] The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art, readily modify and / or adapt for various applications such specific embodiments, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.

Claims

CLAIMSWe claim1. A sublingual composition comprising an anti-fibrotic agent for the treatment of anti- fibrotic diseases, disorders or conditions or hypertensive diseases, disorders or conditions.

2. The composition of claim 1, wherein an anti-fibrotic agent entrapped niosomes.

3. The composition of claim 1, wherein an anti -fibrotic agent is for the treatment of anti- fibrotic diseases, disorders or conditions.

4. The composition of claim 1, wherein an anti-fibrotic agent is for the treatment of hypertensive diseases, disorders or conditions.

5. The composition of claim 1, wherein an anti-fibrotic agent is a TGF-P (Transforming growth factor) inhibitor.

6. The composition of claim 1, wherein an anti -fibrotic agent is selected from pirfenidone, nintedanib or its analogues or a tautomer thereof, prodrug thereof, N-oxide thereof, a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

7. The composition of claim 1, wherein an anti -fibrotic agent is selected from pirfenidone, or a pharmaceutically acceptable salt thereof.

8. The composition of claim 1, wherein an anti-fibrotic agent is selected from nintedanib, or a pharmaceutically acceptable salt thereof.

9. The composition of claim 1, wherein anti-fibrotic diseases, disorders or conditions is selected from including but not limited to lung fibrosis or pulmonary fibrosis, liver fibrosis, heart fibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis, bone marrow fibrosis, kidney fibrosis, skin fibrosis, scleroderma, interstial lung disorders or systemic sclerosis.

10. The composition of claim 1, wherein anti-fibrotic diseases, disorders or conditions is selected from Idiopathic pulmonary fibrosis (IPF).

11. The composition of claim 1, wherein hypertensive diseases, disorders or conditions is selected from included but not limited to essential hypertension (primary hypertension), secondary hypertension, hypertensive heart disease, hypertensive retinopathy, hypertensive kidney disease (nephrosclerosis), hypertensive cerebrovascular disease, and pulmonary hypertensive diseases.

12. The composition of claim 1, wherein hypertensive diseases, disorders or conditions is selected from pulmonary hypertensive diseases.

13. The composition of claim 1, wherein hypertensive diseases, disorders or conditions is selected from Pulmonary arterial hypertension (PAH).

14. A sublingual composition comprising an anti-fibrotic agent pharmaceutically acceptable excipients for the treatment of anti-fibrotic diseases, disorders or conditions or hypertensive diseases, disorders or conditions.

15. The composition of claim 1-14, wherein the composition comprises an anti-fibrotic agent of about 1% to about 80% (w / w).

16. The composition of claim 1-15, wherein the composition comprises pirfenidone, nintedanib or a pharmaceutically acceptable salt thereof of about 1% to about 80% (w / w).

17. The composition of claim 1-15, wherein the composition comprises pirfenidone, or a pharmaceutically acceptable salt thereof of about 10% to about 75% (w / w).

18. The composition of claim 1-15, wherein the composition comprises pirfenidone, or a pharmaceutically acceptable salt thereof of about 15% to about 75% (w / w).

19. The composition of claim 1-15, wherein the composition comprises pirfenidone, or a pharmaceutically acceptable salt thereof of about 5%, 10%, 15%, 20, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% (w / w).

20. The composition of claim 1-15, wherein the composition comprises nintedanib or a pharmaceutically acceptable salt thereof of about 10% to about 75% (w / w).

21. The composition of claim 1-15, wherein the composition comprises nintedanib or a pharmaceutically acceptable salt thereof of about 15% to about 75% (w / w).

22. The composition of claim 1-15, wherein the composition comprises nintedanib or a pharmaceutically acceptable salt thereof of about 5%, 10%, 15%, 20, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% (w / w).

23. The composition of claim 1-22, wherein the composition comprises about 5% to about 50% (w / w) of a film forming polymer.

24. The composition of claim 1-22, wherein the composition comprises about 8% to about 50% (w / w) of a film forming polymer.

25. The composition of claim 1-22, wherein the composition comprises about 0% to about 20% (w / w) of a plasticizer.

26. The composition of claim 1-22, wherein the composition comprises about 0% to about 20% (w / w) of a buffering agent.

27. The composition of claim 1-22, wherein the composition comprises about 0% to about 20% (w / w) of a binder.

28. The composition of claim 1-22, wherein the composition comprises about 1% to about 8% (w / w) of a binder.

29. The composition of claim 1-22, wherein the composition comprises about 0% to about 20% (w / w) of an acidifier.

30. The composition of claim 1-22, wherein the composition comprises about 1% to about 9% (w / w) of an acidifier.

31. The composition of claim 1-22, wherein the composition comprises about 0% to about 6% (w / w) of a saliva stimulating agent.

32. The composition of claim 1-22, wherein the composition comprises about 3% to about 35% (w / w) of a sweetener agent.

33. The composition of claim 1-22, wherein the composition comprises about 7% to about 31% (w / w) of a sweetener agent.

34. The composition of claim 1-22, wherein the composition comprises about 0% to about 10% (w / w) of a flavouring agent.

35. The composition of claim 1-22, wherein the composition comprises about 0.01% to about 1% (w / w) of a flavouring agent.

36. The composition of claim 1-22, wherein the composition comprises about 0% to about 1% (w / w) of a colouring agent.

37. The composition of claim 1-22, wherein the composition comprises about 0.01% to about 0.1% (w / w) of a colouring agent.

38. A method of preparation of a sublingual film composition comprising of an anti-fibrotic agent and pharmaceutically acceptable excipients for the treatment of anti-fibrotic diseases, disorders or conditions or hypertensive diseases, disorders or conditions.

39. The method of claim 38, wherein an anti-fibrotic agent is selected from pirfenidone, nintedanib or a pharmaceutically acceptable salt thereof40. The method of claim 38, wherein an anti -fibrotic agent is selected from pirfenidone, or a pharmaceutically acceptable salt thereof41. The method of claim 38, wherein the pharmaceutically acceptable excipients are selected from may include, but not limited to one or more of the following: a Film forming polymer, a plasticizer, a Buffering agent, a Binder, Acidifier, a Saliva stimulating agent, a Sweetener, a Flavouring agent, a Colouring agent and / or a solvent.

42. The method of claim 38, wherein anti-fibrotic diseases, disorders or conditions is selected from including but not limited to lung fibrosis or pulmonary fibrosis, liver fibrosis,heart fibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis, bone marrow fibrosis, kidney fibrosis, skin fibrosis, scleroderma, interstial lung disorders or systemic sclerosis.

43. The method of claim 38, wherein anti-fibrotic diseases, disorders or conditions is selected from Idiopathic pulmonary fibrosis (IPF).

44. The method of claim 38, wherein hypertensive diseases, disorders or conditions is selected from included but not limited to essential hypertension (primary hypertension), secondary hypertension, hypertensive heart disease, hypertensive retinopathy, hypertensive kidney disease (nephrosclerosis), hypertensive cerebrovascular disease, and pulmonary hypertensive diseases.

45. The method of claim 38, wherein hypertensive diseases, disorders or conditions is selected from pulmonary hypertensive diseases.

46. The method of claim 38, wherein hypertensive diseases, disorders or conditions is selected from Pulmonary arterial hypertension (PAH).

Images