DESC:CAPSULE IN CAPSULE PRODUCT FOR CAPSULE BASED DRY POWDER INHALATION FORMULATION

FIELD OF THE INVENTION
[0001] The present disclosure pertains to the field of capsules, more specifically to capsule in capsule product for capsule based dry powder inhalation formulation.

BACKGROUND OF THE INVENTION
[0002] Pulmonary drug delivery is currently the focus of research and development because of its potential to produce maximum therapeutic benefit to patients by directing the drug straight to the lung disease site. Among all the available delivery options, one popular, proven and convenient inhaler device is the capsule-based dry powder inhaler (cDPI) for the treatment of an increasingly diverse range of lung related diseases. cDPIs use a hard capsule that contains a powder formulation which consists of a mixture of a micronized drug and a carrier usually the lactose, known for its good lung tolerance. The capsule is either inserted into the device during manufacturer which is rare due to the complexities in the manufacturing or by the patient prior to use. After perforating, opening or cut the capsule in the device, patients take a deep and rapid breath to inhale the powder, using air as the vector of drug displacement. The system is simple, relatively cheap and characterized by a lower carbon footprint than that of pressurized metered dose inhalers.
[0003] Pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs) and nebulizers are the main categories of inhaled drug delivery systems, each class with its unique strengths and weaknesses. This classification is based on the physical state of the formulation as well as on the type of device used to meter, deliver and aerosolise the dose of product to the lungs. pMDIs and DPIs, containing a suspended or dissolved drug in a propellant or a drug as in dry powder form, are the most widely used drug delivery systems for lung disease treatment.
[0004] The development of the first commercially available inhaler, in the form of a pMDI, dates back to 1956. Although this was an innovation for the therapy of pulmonary diseases, concerns arose around the 1970s when the contribution of chlorofluorocarbon (CFC) propellants to the depletion of the ozone layer led to their substitution by more environmentally friendly hydrofluoroalkane (HFA) gases, still used nowadays [2]. These inhalers generate a drug aerosol upon actuation and the drug is suspended or solubilized in the propellant. In the case of suspension pMDIs, the high variability and inconsistency of the emitted dose when the inhalers are not shaken properly suggest the importance of following the leaflet instructions and of training the patient on this topic. Moreover, the coordination between the device actuation and inhalation is a key element for the efficacy of particle deposition in the lung and for the overall disease treatment. DPIs were developed with the aim of overcoming pMDI limitations which used two pins to create opposing holes in the sidewall of the body of a gelatin capsule loading the powder dose. General DPIs have used either pairs of pins, to make single holes in the sidewalls or two sets of four pins to make multiple holes in both domed body and cap. In each of these devices, the insertion of the needle into the capsule wall is a manual mechanical process controlled by the patient. Once the contents of the capsule have been made available for its release, the patient’s inhalation act generates turbulent air flows in the inhaler, which cause the capsule to move and release the powder contained therein.
[0005] DPIs are mainly used in the treatment of respiratory diseases such as asthma, COPD and, more recently, cystic fibrosis. The active medicament as a dry powder is delivered using a device that enables its aerosolization in a suitable aerodynamic size for lung deposition (less than 5 microns) and an adequate delivery to the lung. Moreover, they enable the administration and deposition of high drug doses within the lungs, thereby limiting the incidence of both local and systemic side effects.
[0006] Asthma is chronic inflammatory disease, characterized by inflammation and bronchoconstriction (i.e., narrowing of airways to lungs) and muscle around tighten. COPD (chronic obstructive pulmonary disease) is general term encompassing, chronic bronchitis, emphysema, and COAD (chronic obstructive airways disease). COPD is chronic slowly progressive disorder characterized by airways obstructions which does not change markedly over several months. DPI based drug delivery has been shown to be attractive and effective in treating local lung diseases like asthma, chronic obstructive pulmonary diseases (COPD) and cystic fibrosis (CF). It has also been widely accepted and used in clinical practices. Along with application in management of asthma and COPD, it manages to drive attention to explore the inhalation therapy for systemic diseases. Potential for delivering of drug for other systemic diseases, such as Diabetes Mellitus, Parkinson’s disease and Schizophrenia has been explored in the past two decades.
[0007] Pulmonary drug delivery is currently the focus of accelerated research and development because of the potential to produce maximum therapeutic benefit to patients by directly targeting drug to the site of pathology in the lungs. The current coronavirus (covid-19) pandemic also has increased such interest and is triggering more potential applications of dry powder inhalation therapy in vaccines and antivirus drugs, treatment options include reliever (i.e., used for fast onset of action) and controller (i.e., taken daily to maintain) medication. Widely used controller medication for the treatment of chronic obstructive pulmonary disease (COPD) includes bronchodilators, including anticholinergics such as Ipratropium, Tiotropium, and glycopyrronium, which works by relaxing the muscles in the lung widening the airways. Other controller medications may be indicated including combinations of long-acting beta 2 adrenoreceptor agonists (LABA) i.e. salmeterol, formoterol and inhaled corticosteroid (ICS) i.e. beclomethasone, budesonide. Beta 2 long acting adrenoreceptor agonists (LABA) inhibits the secretion of hypersensitivity mediators from mast cells which shows bronchodilation by direct acting on airways and smooth muscle. Inhaled corticosteroid (ICS) suppress inflammation mainly by switching off multiple activated inflammatory genes.
[0008] Combination therapy has been proven to be clinically beneficial for treating asthma and COPD, and as a result, more combination products are now commercially available and being developed in clinical trials around the world. More recently, there has been a trend towards the use of combination therapy in the delivery of inhaled medications. This could potentially contribute to the convenience of drug administration as well as confer synergistic effect, leading to better treatment adherence and clinical outcomes. Combination therapy has not only increased the efficacy of the therapeutic effect but also decrease the duration and adverse effect of individual drug. To counteract the development of resistance against the multiple drugs are lowered as compared to single drug. In terms of economic evaluation, combination therapy may be considered as more cost effective than the medications administered separately. With all these benefits in view, combination therapy has been applied widely by clinicians in practice to treat various human diseases, such as diabetes, hypertension, schizophrenia, cancer as well as respiratory diseases etc.
[0009] Presently industries are more prone to adapt the combination therapy over single drug therapy. However, development of combination inhaled formulation is very complex and challenging. From reported literature, studies done on different capsule variants having combination of inhaled formulations showed a decrease in percent drug assay and an increase in total impurity due to their incompatibility and the reactivity among themselves. All combination of inhaled formulations available in market are having minimum two drugs enclosed within the same capsule. This may result in drug-drug interaction, drug-degradation due to storage conditions. These all can possibly be the reasons for contributing to impurities and other issues reported in the literature.
[00010] Thus, there is felt a need for formulation which can reduce total impurities and achieve maximum therapeutic efficacy and drug stability.
Problem Statement
[00011] The stability of multiple API formulations in single-capsule DPI systems poses a significant barrier to their effectiveness. When multiple active pharmaceutical ingredients (APIs) are combined within a single capsule, there is a risk of chemical interactions that can lead to impurity formation and degradation over time. For instance, interactions between certain bronchodilators and corticosteroids can accelerate impurity generation, compromising the therapeutic quality and shelf-life of the product. Such instability not only affects the safety profile but also challenges regulatory compliance, as manufacturers must continuously monitor and control impurity levels to meet quality standards.
[00012] Moreover, these stability issues become especially pronounced under varying environmental conditions, such as relative humidity or temperature fluctuations, which are common during storage and patient use. These factors contribute to variability in dose delivery, potentially diminishing the therapeutic effects and impacting patient outcomes.
[00013] To overcome these formulation and stability challenges, a novel approach to DPI design is required—one that can maintain the integrity of each API while ensuring consistent, effective delivery. The capsule-in-capsule (CiC) formulation presents a breakthrough solution to these challenges by isolating each API within its own compartment inside a primary capsule shell. This configuration minimizes cross-reactivity and impurity formation, offering improved stability and allowing for controlled, multiple API delivery. The CiC formulation could therefore transform DPI technology, addressing a critical gap in the effective delivery of complex respiratory and other therapies.

SUMMARY OF THE INVENTION
[00014] The present aspect in an embodiment discloses a capsules based dry powder inhaler (DPI) system. The DPI system comprises a first capsule containing a first pharmaceutical formulation and a second capsule contained within the first capsule containing a second pharmaceutical formulation.
[00015] In another aspect of the present invention, disclosed is a pharmaceutical formulation for a dry powder inhaler. The formulation comprises a first active pharmaceutical ingredient (API) formulated in a first dry powder formulation and a second active pharmaceutical ingredient (API) formulated in a second dry powder formulation. The first formulation and the second formulation are separated into distinct capsules within a capsule-in-capsule system, and the APIs are released in a controlled manner upon inhalation.
[00016] The first pharmaceutical formulation comprises of two or more active pharmaceutical ingredient (API) and at least one excipient for stabilizing the API. The second pharmaceutical formulation also comprises two or more API and at least one excipient for stabilizing the API. The first formulation and the second formulation are housed in separate capsules to prevent direct contact with each other until the capsules are ruptured by an external inhalation device.
DETAILED DESCRIPTION OF THE INVENTION
[00017] The following is a detailed description of embodiments of the present disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[00018] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[00019] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[00020] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[00021] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
[00022] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
[00023] All methods described herein can be performed in suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[00024] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[00025] Various terms are used herein. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[00026] The word ‘capsule’ is derived from the latin capsula, meaning a small box. In pharmacy, the word is used to describe an edible package made from gelatin or other suitable material which is filled with medicines to produce a unit dosage. Capsules are a convenient way to give powdered medications for various reasons such as they conceal unpleasant tastes or textures and also keep the formulations pure and sterile. A capsule is a solid oral dosage form in which the active ingredients and diluents are contained in a two-piece hard shell, usually made of gelatin. After the two pieces are separated, the body piece is filled with the dry powder ingredients and the cap is then replaced.
[00027] The dry powder for the inhalation contains a mixture of the micronized drug and larger carrier lactose particle required to improve the flow property of powder. It is prepared mainly by two methods: by direct adsorption of active on lactose carrier and by spray during the active moiety on carrier. The capsule act as a suitable container for dry powder for inhalation.
[00028] In accordance with the present invention, the formulation is designed as a capsule-in-capsule system for a capsule-based dry powder inhaler (cDPI) system. The term "capsule-in-capsule" refers to a unique arrangement in which a smaller inner capsule, containing a second formulation, is enclosed within a larger outer capsule containing the first formulation. This configuration is not limited by conventional size definitions, and the term “capsule” is inclusive of both macroscopic capsules (measuring in millimeters) as well as microcapsules or nanocapsules, which are often employed for immediate or controlled release of pharmaceuticals at the molecular level. The key advantage of this design is the ability to physically separate incompatible formulations or APIs within each respective capsule, allowing for simultaneous administration upon capsule rupture, thereby achieving a multi-phase release profile by preventing the interaction within the two incorporated APIs with improved therapeutic outcomes.
[00029] The invention provides a modular, multi-compartment capsule system, wherein different formulations are housed in distinct capsule layers. These capsules are designed with impermeable walls that effectively isolate the formulations until the point of administration, typically when the capsules are mechanically fractured/ruptured. The rupture of both the outer and inner capsules is engineered to occur synchronously or in a controlled sequence, allowing the APIs to be brought into contact only when the capsules are exposed to the airflow generated by the patient’s inhalation, ensuring that the active ingredients mix effectively before reaching the pulmonary target site. This system enhances biopharmaceutical performance by enabling precise modulation of drug kinetics, particularly when dealing with incompatible drugs or when a staggered or sequential release of multiple APIs is required.
[00030] The invention can be extended to systems where more than two formulations (comprising multiple APIs) are contained in multiple capsules arranged within a larger capsule. For example, the outer capsule can contain a mixture of two or more APIs, while the inner capsules can individually house separate APIs. This enables flexible combinations of drugs, for instance, in diseases requiring combination therapy, without compromising the stability of the individual components.
[00031] In one embodiment, the invention utilizes a dual capsule system, wherein the outer capsule is relatively larger and houses the first formulation, while a smaller capsule inside it contains the second formulation. The dimensions of the capsules are selected on the basis of the suitability and efficiency of puncturing device. The capsule wall integrity is a critical factor in ensuring the no contact between the APIs, the shell material may vary in composition or thickness to modulate the strength and rupture dynamics. For example, an outer capsule wall may rupture first, allowing the active ingredient in the inner capsule to be released with minimal delay. In either event, the fracture of one capsule should be accompanied by the fracture of the second capsule. Thus, the present invention achieves both controlled and multi-phase release for combination of formulations. Moreover, delivery of incompatible APIs, patient convenience, compliance and cost-effective therapy is also achieved.
[00032] Upon administration, the capsules are subjected to puncturing by a DPI device, which is equipped with a puncturing mechanism that interacts with the capsule to release the powder content. The puncturing mechanism may comprise. side-puncturing pins, where the capsule is punctured from the side using one or more pins, such as two, three, or four pins.
[00033] Once punctured, the formulation from both the capsules is allowed to exit through the opening and enters the airflow path of the DPI device. The device is further equipped with a mouthpiece, which is structurally configured to direct the airflow into the user's respiratory system, ensuring that the released powder is inhaled and delivered directly to the lungs.
[00034] The size and structural integrity of the capsules are determined based on several factors, including the required volume of active ingredients, the rupture mechanism of device used and the device’s aerodynamic characteristics. The relative size of the inner and outer capsules is optimized to ensure that the release of each formulation occurs in the correct sequence, with sufficient inhalation force generated by the patient’s breath to rupture the capsule shells efficiently.
[00035] In a preferred embodiment of the present invention, a capsule-in-capsule composition for the administration of combination therapies for respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), or other obstructive pulmonary conditions or any other therapeutic condition where it is treated through inhalation route.. The composition comprises:
? a first capsule containing a formulation comprising a corticosteroid, such as Budesonide, Fluticasone Propionate, Beclomethasone Dipropionate, or Levosalbutamol sulfate, and appropriate excipients for stabilizing and enhancing the performance of the formulation; and
? a second capsule containing a bronchodilator, such as Formoterol Fumarate, Salmeterol, Levosalbutamol, or Ipratropium Bromide, along with excipients designed to optimize the release properties and ensure compatibility with the first formulation.
[00036] In an exemplary embodiment, a capsule-in-capsule form comprises a first capsule and a second capsule which is located within the first capsule, wherein the first capsule comprising a first formulation held between the first and second capsule and comprising a second formulation held in the second capsule, and wherein the first formulation and the second formulation is a combination selected from the group of Formoterol Fumarate + Budesonide, Salmeterol + Fluticasone Propionate, Levosalbutamol + Beclomethasone Dipropionate and Ipratropium Bromide + Levosalbutamol sulphate not limited to but can be extend to the other potential inhalation drug combination.
[00037] In one embodiment, the first formulation or the second formulation comprises pharmaceutically acceptable excipients, including but not limited bulking agents (e.g., lactose monohydrate, mannitol, trehalose), carrier particles (e.g., coarse lactose, maltodextrins), glidants (e.g., magnesium stearate, colloidal silicon dioxide), lubricants (e.g., magnesium stearate), stabilizers (e.g., sucrose, dextran, hydroxypropyl methylcellulose), moisture regulators (e.g., silica gel, hygroscopic agents), and surfactants (e.g., polysorbates like Tween 80, lecithin).
[00038] In another embodiment of the present invention, the excipients may include solvents, dispersing agents, and buffering agents to ensure solubility, stability, and consistent particle dispersion. The excipients must be chosen with consideration to their compatibility with the active ingredients to avoid adverse reactions or unwanted interactions that may affect drug efficacy.
[00039] In yet another embodiment of the present invention, at least one carrier is selected from the group consisting of, but not limited to microcrystalline cellulose, microcrystalline cellulose pellet, mannitol, spray-dried mannitol, lactose, inhalation grade lactose, monohydrated lactose, anhydrous lactose, Trehalose, maltodextrins, Cyclodextrins, magnesium stearate, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
[00040] In yet another embodiment of the present invention, at least one bulking agent is selected from the group consisting of, but not limited to, talc, mannitol, maltitol, sorbitol, mixtures thereof.
[00041] In yet another embodiment of the present invention, at least one solvent is selected from the group consisting of, but not limited to, water, ethanol, propylene glycol, or mixtures thereof.
[00042] In yet another embodiment of the present invention, at least one buffering agent is selected from the group consisting of, but not limited to, citric acid, tartaric acid, ascorbic acid, or mixtures thereof.
[00043] In yet another embodiment of the present invention, at least one dispersing agent is selected from the group consisting of, but not limited to, amino acid, hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium Carboxy methyl cellulose or mixtures thereof.
[00044] The DPI device used in conjunction with the CiC system is configured to puncture both the capsules simultaneously, thereby releasing the formulation effectively. The puncturing mechanism ensures that the powder is efficiently aerosolized for inhalation. In embodiment, the puncturing mechanism may comprise a side-puncturing pin or a multi-pin design, with the pins being arranged to puncture the capsule in such a way that the formulation is not compromised.
[00045] Once the capsules are punctured, the powder is directed through the mouthpiece of the device from both the capsules in the CiC system. The device is configured to deliver the powder to the lungs efficiently, using aerodynamic properties to ensure that the powder is properly inhaled. The mouthpiece structure of the device is designed to allow the user to exhale inside the device, thereby creating the necessary airflow for the powder to be properly inhaled into the respiratory tract.
[00046] This embodiment of the invention relates to a capsule-in-capsule (CiC) formulation where the capsules used are either gelatin or hydroxypropyl methylcellulose (HPMC) or Pullulan polymers. The capsules are designed to provide effective delivery of the active pharmaceutical ingredients (APIs) by ensuring that the inner capsule containing one or more APIs is housed within an outer capsule. The sizes of the capsules may vary depending on the formulation requirements, with two distinct capsule sizes being utilized in this embodiment to accommodate the needs of the formulation and compatibility with device.
[00047] The outer capsule is larger in size, typically size 2 or size 3, while the inner capsule is smaller, typically size 4 or size 5. This is not limited but can be extended to any capsules sizes which is suitable for application. This size combination allows for flexibility in accommodating various formulations, ensuring that the APIs and excipients are appropriately contained within the inner capsule while maintaining the stability of the system. Specifically, two configurations are possible:
1. Size 4 capsule encapsulated within a size 2 capsule, or
2. Size 5 capsule encapsulated within a size 3 capsule.
[00048] The capsule design ensures that the inner capsule is able to move freely within the outer capsule without obstruction. This freedom of movement is critical to avoid hindrance during the release of the powder formulation from the device. The movement of the inner capsule is essential for maintaining the flowability of the powder during inhalation, ensuring that all the contents are efficiently delivered to the lungs.
[00049] The DPI device used in conjunction with the CiC formulation is designed to be compatible with the specific capsule sizes used in the system. In this embodiment, a side-puncturing or dome puncturing device is employed, which is specifically configured to puncture both the inner and outer capsules simultaneously. The device utilizes a side-puncturing pin mechanism, wherein the length of the puncturing pin is sufficiently long to penetrate both the outer capsule, and the inner capsule contained within.
[00050] The successful simultaneous puncturing of both capsules is essential to the effective delivery of the formulation. The device is configured such that when the puncturing pins are activated, they create openings in both capsules, allowing the powder inside to be released effective manner. The precise alignment of the puncturing mechanism is critical to ensure that the inner capsule is punctured at the right moment, releasing the APIs into the airflow of the device.
[00051] The hollow space between the inner and outer capsules plays a crucial role in the functionality of the system. It provides a buffer zone that allows the inner capsule to remain mobile within the outer capsule. This mobility ensures that there is no obstruction to the flow of powder from the inner capsule to the outside, preventing any potential blockage that may interfere with the powder’s aerodynamic release during inhalation.
[00052] The design of the capsule-in-capsule (CiC) system in this embodiment ensures that the inner and outer capsules can be punctured simultaneously without interference, providing an efficient and effective delivery of the active pharmaceutical ingredients to the lungs. The capsule size combination (size 4 or size 5 inner capsules within size 2 or size 3 outer capsules) offers flexibility for different formulations while ensuring that the formulation is delivered in a stable and effective manner. The compatibility of the device, with the side-puncturing or dome punctuing pin and appropriately sized capsule puncturing mechanism, is critical to the successful operation of the system and to ensuring the proper release of the powder formulation for inhalation.
[00053] In an exemplary embodiment of the present invention, the capsule in capsule product for cDPI (capsule based dry powder inhalation) formulation comprises the following:
Formula 1:
First Capsule Contents
Amounts
Budesonide (1-5 µm) 0.200 mg
Inhalation grade lactose 1 (5- 120 µm) 12.800 mg
Inhalation grade lactose 2 (75- 300 µm) 12.000 mg
Total Weight of First Capsule 25.000 mg

Second Capsule Contents Amounts
Formoterol Fumarate (1-5 µm) 0.006 mg
Inhalation grade lactose 1 (5- 120 µm) 12.994 mg
Inhalation grade lactose 2 (75- 300 µm) 12.000 mg
Total Weight of Second Capsule 25.000 mg

Formula 2:
First Capsule Contents
Amounts
Budesonide (1-5 µm) 0.200 mg
Inhalation grade lactose 1 (25-150 µm) 8.500 mg
Inhalation grade lactose 2 (55-200 µm) 6.300 mg
Total Weight of First Capsule 15.000 mg

Second Capsule Contents Amounts
Formoterol Fumarate (1-5 µm) 0.006 mg
Inhalation grade lactose 1 (25-150 µm) 7.596 mg
Inhalation grade lactose 2 (55-200 µm) 7.398 mg
Total Weight of Second Capsule 15.000 mg

Formula 3:
First Capsule Contents
Amounts
Budesonide (1-5 µm) 0.200 mg
Inhalation grade lactose 1 (5 -120 µm) 13.940 mg
Inhalation grade lactose 2 (50-165 µm) 10.860 mg
Total Weight of First Capsule 25 mg

Second Capsule Contents Amounts
Formoterol Fumarate (1-5 µm) 0.006 mg
Inhalation grade lactose 1 (5 -120 µm) 7.744 mg
Inhalation grade lactose 2 (50-165 µm) 7.250 mg
Total Weight of Second Capsule 15.000 mg

Formula 4:
First Capsule Contents
Amounts
Budesonide (1-5 µm) 0.200 mg
Inhalation grade lactose 1 (5 -120 µm) 7.800 mg
Inhalation grade lactose 2 (75-300 µm) 7.000mg
Total Weight of First Capsule 15.000 mg

Second Capsule Contents Amounts
Formoterol Fumarate (1-5 µm) 0.006 mg
Inhalation grade lactose 1 (5 -120 µm) 12.194 mg
Inhalation grade lactose 2 (75-300 µm) 12.800 mg
Total Weight of Second Capsule 25.000 mg

Formula 5:
First Capsule Contents
Amounts
Budesonide (1-5 µm) 0.200 mg
Inhalation grade lactose 1 (5 -120 µm) 4.800 mg
Total Weight of First Capsule 5.000 mg

Second Capsule Contents Amounts
Formoterol Fumarate (1-5 µm) 0.006 mg
Inhalation grade lactose 1 (5 -120 µm) 4.996 mg
Total Weight of Second Capsule 5.000 mg

Formula 6:
First Capsule Contents
Amounts
Fluticasone propionate (1-5 µm) 0.250 mg
Inhalation grade lactose 1 (5- 120 µm) 12.745 mg
Inhalation grade lactose 2 (75- 300 µm) 12.005 mg
Total Weight of First Capsule 25.000 mg

Second Capsule Contents Amounts
Salmeterol (1-5 µm) 0.025 mg
Inhalation grade lactose 1 (5- 120 µm) 12.990 mg
Inhalation grade lactose 2 (75- 300 µm) 11.985 mg
Total Weight of Second Capsule 25.000 mg

Formula 7:
First Capsule Contents
Amounts
Fluticasone propionate (1-5 µm) 0.250 mg
Inhalation grade lactose 1 (25-150 µm) 7.750 mg
Inhalation grade lactose 2 (55-200 µm) 7.000 mg
Total Weight of First Capsule 15.000 mg

Second Capsule Contents Amounts
Salmeterol (1-5 µm) 0.025 mg
Inhalation grade lactose 1 (25-150 µm) 8.120 mg
Inhalation grade lactose 2 (55-200 µm) 6.855 mg
Total Weight of Second Capsule 15.000 mg

Formula 8:
First Capsule Contents
Amounts
Fluticasone propionate (1-5 µm) 0.250 mg
Inhalation grade lactose 1 (5 -120 µm) 12.775 mg
Inhalation grade lactose 2 (50-165 µm) 11.975 mg
Total Weight of First Capsule 25 mg

Second Capsule Contents Amounts
Salmeterol (1-5 µm) 0.025 mg
Inhalation grade lactose 1 (5 -120 µm) 7.550 mg
Inhalation grade lactose 2 (50-165 µm) 7.425 mg
Total Weight of Second Capsule 15.000 mg

Formula 9:
First Capsule Contents
Amounts
Fluticasone propionate (1-5 µm) 0.250 mg
Inhalation grade lactose 1 (5 -120 µm) 7.900 mg
Inhalation grade lactose 2 (75-300 µm) 6.850 mg
Total Weight of First Capsule 15.000 mg

Second Capsule Contents Amounts
Salmeterol (1-5 µm) 0.025 mg
Inhalation grade lactose 1 (5 -120 µm) 12.975 mg
Inhalation grade lactose 2 (75-300 µm) 12.000 mg
Total Weight of Second Capsule 25.000 mg

Formula 10:
First Capsule Contents
Amounts
Fluticasone propionate (1-5 µm) 0.250 mg
Inhalation grade lactose 1 (5 -120 µm) 4.750 mg
Total Weight of First Capsule 5.000 mg

Second Capsule Contents Amounts
Salmeterol (1-5 µm) 0.025 mg
Inhalation grade lactose 1 (5 -120 µm) 4.975 mg
Total Weight of Second Capsule 5.000 mg

Formula 11:
First Capsule Contents
Amounts
Levosalbutamol (1-5 µm) 0.050 mg
Inhalation grade lactose 1 (5- 120 µm) 12.950 mg
Inhalation grade lactose 2 (75- 300 µm) 12.000 mg
Total Weight of First Capsule 25.000 mg

Second Capsule Contents Amounts
Beclomethasone (1-5 µm) 0.050 mg
Inhalation grade lactose 1 (5- 120 µm) 12.950 mg
Inhalation grade lactose 2 (75- 300 µm) 12.000 mg
Total Weight of Second Capsule 25.000 mg

Formula 12:
First Capsule Contents
Amounts
Levosalbutamol (1-5 µm) 0.050 mg
Inhalation grade lactose 1 (25-150 µm) 7.550 mg
Inhalation grade lactose 2 (55-200 µm) 7.500 mg
Total Weight of First Capsule 15.000 mg

Second Capsule Contents Amounts
Beclomethasone (1-5 µm) 0.050 mg
Inhalation grade lactose 1 (25-150 µm) 7.550 mg
Inhalation grade lactose 2 (55-200 µm) 7.500 mg
Total Weight of Second Capsule 15.000 mg

Formula 13:
First Capsule Contents
Amounts
Levosalbutamol (1-5 µm) 0.050 mg
Inhalation grade lactose 1 (5 -120 µm) 12.950 mg
Inhalation grade lactose 2 (50-165 µm) 12.000 mg
Total Weight of First Capsule 25 mg

Second Capsule Contents Amounts
Beclomethasone (1-5 µm) 0.050 mg
Inhalation grade lactose 1 (5 -120 µm) 7.550 mg
Inhalation grade lactose 2 (50-165 µm) 7.500 mg
Total Weight of Second Capsule 15.000 mg

Formula 14:
First Capsule Contents
Amounts
Levosalbutamol (1-5 µm) 0.050 mg
Inhalation grade lactose 1 (5 -120 µm) 7.750 mg
Inhalation grade lactose 2 (75-300 µm) 7.200mg
Total Weight of First Capsule 15.000 mg

Second Capsule Contents Amounts
Beclomethasone (1-5 µm) 0.050 mg
Inhalation grade lactose 1 (5 -120 µm) 12.500 mg
Inhalation grade lactose 2 (75-300 µm) 12.450 mg
Total Weight of Second Capsule 25.000 mg

Formula 15:
First Capsule Contents
Amounts
Levosalbutamol (1-5 µm) 0.050 mg
Inhalation grade lactose 1 (5 -120 µm) 4.950 mg
Total Weight of First Capsule 5.000 mg

Second Capsule Contents Amounts
Beclomethasone (1-5 µm) 0.050 mg
Inhalation grade lactose 1 (5 -120 µm) 4.950 mg
Total Weight of Second Capsule 5.000 mg

Formula 16:
First Capsule Contents
Amounts
Levosalbutamol sulphate (1-5 µm) 0.100 mg
Inhalation grade lactose 1 (5- 120 µm) 12.600mg
Inhalation grade lactose 2 (75- 300 µm) 12.300 mg
Total Weight of First Capsule 25.000 mg

Second Capsule Contents Amounts
Ipratropium bromide (1-5 µm) 0.040 mg
Inhalation grade lactose 1 (5- 120 µm) 12.560 mg
Inhalation grade lactose 2 (75- 300 µm) 12.400 mg
Total Weight of Second Capsule 25.000 mg

Formula 17:
First Capsule Contents
Amounts
Levosalbutamol sulphate (1-5 µm) 0.100 mg
Inhalation grade lactose 1 (25-150 µm) 7.750 mg
Inhalation grade lactose 2 (55-200 µm) 7.150 mg
Total Weight of First Capsule 15.000 mg

Second Capsule Contents Amounts
Ipratropium bromide (1-5 µm) 0.040 mg
Inhalation grade lactose 1 (25-150 µm) 7.500 mg
Inhalation grade lactose 2 (55-200 µm) 7.460 mg
Total Weight of Second Capsule 15.000 mg

Formula 18:
First Capsule Contents
Amounts
Levosalbutamol sulphate (1-5 µm) 0.100 mg
Inhalation grade lactose 1 (5 -120 µm) 12.500 mg
Inhalation grade lactose 2 (50-165 µm) 12.400 mg
Total Weight of First Capsule 25 mg

Second Capsule Contents Amounts
Ipratropium bromide (1-5 µm) 0.040 mg
Inhalation grade lactose 1 (5 -120 µm) 7.560 mg
Inhalation grade lactose 2 (50-165 µm) 7.400 mg
Total Weight of Second Capsule 15.000 mg

Formula 19:
First Capsule Contents
Amounts
Levosalbutamol sulphate (1-5 µm) 0.100 mg
Inhalation grade lactose 1 (5 -120 µm) 7.900 mg
Inhalation grade lactose 2 (75-300 µm) 7.000 mg
Total Weight of First Capsule 15.000 mg

Second Capsule Contents Amounts
Ipratropium bromide (1-5 µm) 0.040 mg
Inhalation grade lactose 1 (5 -120 µm) 12.460 mg
Inhalation grade lactose 2 (75-300 µm) 12.500 mg
Total Weight of Second Capsule 25.000 mg

Formula 20:
First Capsule Contents
Amounts
Levosalbutamol sulphate (1-5 µm) 0.100 mg
Inhalation grade lactose 1 (5 -120 µm) 4.900 mg
Total Weight of First Capsule 5.000 mg

Second Capsule Contents Amounts
Ipratropium bromide (1-5 µm) 0.040 mg
Inhalation grade lactose 1 (5 -120 µm) 4.960 mg
Total Weight of Second Capsule 5.000 mg

Formula 21:
First Capsule Contents
Amounts
Glycopyrronium (1-5 µm) 0.025 mg
Formoterol fumarate (1-5 µm) 0.015 mg
Inhalation grade lactose 1 (5 -120 µm) 12.500 mg
Inhalation grade lactose 2 (75-300 µm) 12.465 mg
Total Weight of First Capsule 25.000 mg

Second Capsule Contents Amounts
Budesonide (1-5 µm) 0.400 mg
Inhalation grade lactose 1 (5 -120 µm) 7.600 mg
Inhalation grade lactose 2 (75-300 µm) 7.000 mg
Total Weight of Second Capsule 15.000 mg

Formula 22:
First Capsule Contents
Amounts
Budesonide (1-5 µm) 0.400 mg
Inhalation grade lactose 1 (5 -120 µm) 12.600 mg
Inhalation grade lactose 2 (75-300 µm) 12.000 mg
Total Weight of First Capsule 25.000 mg

Second Capsule Contents Amounts
Glycopyrronium (1-5 µm) 0.025 mg
Formoterol fumarate (1-5 µm) 0.015 mg
Inhalation grade lactose 1 (5 -120 µm) 7.500 mg
Inhalation grade lactose 2 (75-300 µm) 7.465 mg
Total Weight of Second Capsule 15.000 mg

[00054] Example: Evaluation of Capsule-in-Capsule (CiC) System for Levosalbutamol and Ipratropium in a Dry Powder Inhaler (DPI)
Objective:
The purpose of this experiment is to compare the drug delivery efficiency, fine particle dose (FPD), and stability between the Capsule-in-Capsule (CiC) system and the single capsule formulation containing Levosalbutamol sulphate and Ipratropium Bromide in a Dry Powder Inhaler (DPI).
Materials:
• Levosalbutamol sulfate (100 mcg) in size 4 capsules (inner capsule).
• Ipratropium bromide (40 mcg) in size 2 capsules (outer capsule).
• DPI Device: Two-pin dome puncturing device or side puncturing deice.
• Cascade Impactor: Cascade mass impactor to measure fine particle dose.
• Capsule Materials: Gelatin capsules (size 2 and size 4) or HPMC (Hydroxypropyl Methylcellulose) capsules.
• Flow Rate: 90 L/min.
Method:
1. Preparation of Formulations:
• Single Capsule Formulation (Individual formulation):
Levosalbutamol sulphate (100 mcg) was filled into a single size 2 capsule for the comparative analysis.
• Single Capsule Formulation (Individual formulation):
Ipratropium bromide (40 mcg) was filled into a single size 2 capsule for the comparative analysis.
• Capsule-in-Capsule (CiC) Formulation:
Levosalbutamol (100 mcg) was filled into size 4 capsules (inner capsule), and Ipratropium (40 mcg) was filled into size 2 capsules (outer capsule). The size 4 capsule containing Levosalbutamol was placed inside the size 2 capsule containing Ipratropium.

• Single Capsule Formulation (Combination):
A blend of Levosalbutamol sulphate (100 mcg) and Ipratropium bromide (40 mcg) was filled into a single size 2 capsule for the comparative analysis.

In one sample, Ipratropium bromide, used as a control, is encapsulated in a single Size 2 capsule along with quantity-sufficient excipients, serving as a baseline for release and stability comparisons in a combined API format. Another embodiment includes a formulation of Levosalbutamol alone, also filled into a Size 2 capsule with appropriate excipients, also serving the baseline.
A third embodiment consists of the capsule-in-capsule (CiC) configuration is employed: Levosalbutamol sulfate (100 mcg) is encapsulated in a smaller Size 4 inner capsule, placed inside a larger Size 2 capsule containing Ipratropium bromide (40 mcg). This setup is designed to reduce direct API contact, minimize impurity generation, and ensure optimized aerosol performance.
In the fourth embodiment consist of a blend of Ipratropium bromide and Levosalbutamol combined within a single capsule to evaluate the behavior of the API mixture in standard capsule-based DPI systems.
2. In Vitro Drug Deposition Test:
Each formulation was tested using a cascade impactor to measure the Fine Particle Dose (FPD) and Percent Dose Delivery (PDD).
• Flow rate: 90 L/min was maintained throughout the testing procedure.
• DPI device: A two-pin dome puncturing device was used to puncture the capsules and release the dry powder.
3. Parameters Measured:
• Fine Particle Dose (FPD): The total amount of drug deposited in the fine particle range (<5 microns).
• Percent Dose Delivery (PDD): The percentage of the total drug dose delivered to the appropriate particle size fraction for inhalation.
4. Results:
Table 1: Fine Particle Dose and Percent Dose Delivery for Single Capsule Formulation (Individual formulation)
Drug Fine Particle Dose (mcg) Percent Dose Delivery
Ipratropium Bromide 9.245 mcg 106.48%

Table 2: Fine Particle Dose and Percent Dose Delivery for Single Capsule Formulation (Individual formulation)
Drug Fine Particle Dose (mcg) Percent Dose Delivery
Levosalbutamol Sulphate 21.734 mcg 92.23%

Table 3: Fine Particle Dose and Percent Dose Delivery for Capsule-in-Capsule (CiC) Formulation
Drug Fine Particle Dose (mcg) Percent Dose Delivery
Levosalbutamol Sulphate 22.743 mcg 93.67%
Ipratropium Bromide 9.430 mcg 104.03%
Table 4: Fine Particle Dose and Percent Dose Delivery for Single Capsule Formulation (Combination)
Drug Fine Particle Dose (mcg) Percent Dose Delivery
Levosalbutamol Sulphate 23.867 mcg 92.25%
Ipratropium Bromide 9.640 mcg 97.60%
5. Observations:
Aerodynamic performance and deposition efficiency of the CiC and single-capsule configurations were analyzed using in vitro deposition tests via a cascade impactor at a 90 L/min flow rate, using a two-pin puncturing DPI device. Results indicated that the CiC format delivers fine particle doses (FPD) comparable to those observed with the single-capsule format, underscoring its efficacy in stable API delivery.
The initial cascade impactor study revealed specific FPD outcomes for each configuration. In the first embodiment, where Ipratropium bromide alone was tested, an FPD of 9.246 mcg was achieved, with Levosalbutamol showing an FPD of 21.734 mcg. Impurity analysis for Levosalbutamol revealed a Ipratropium bromide, the single maximum impurity was 0.363%, and total impurities reached 1.7976%, while for Ipratropium bromide single maximum impurity of 0.267% and total impurities of 0.485%.
In the CiC embodiment, cascade impactor results demonstrated an FPD of 22.743 mcg for Levosalbutamol and 9.430 mcg for Ipratropium bromide. Impurity levels in this CiC configuration were found to be favorable, with a single maximum impurity of 0.667% and total impurities of 1.248%, showcasing an improvement over the single-capsule configurations. These findings indicate the CiC format's potential to maintain API stability and minimize impurity levels while ensuring effective aerodynamic performance, which is critical for the reliable and reproducible delivery of multiple APIs in DPI applications.
In the embodiment with a combined API blend of Ipratropium bromide and Levosalbutamol, the FPD was 23.867 mcg for Levosalbutamol and 9.640 mcg for Ipratropium bromide. Relative impurities for the combination blend showed a single maximum impurity level of 0.736% and total impurities 1.370.
It is very evident that the impurity generation can be minimized in the potential formulations by encapsulating these in the individual capsules. This will ease the delivery of the combination drug maximizing the efficacy and in turn patients compliance.
6. Capsule Integrity and Puncturing:
• Both capsule formulations were tested for puncturing performance using the two-pin dome puncturing device.
• The CiC system demonstrated uniform puncture holes on both the inner and outer capsules, ensuring that the active ingredients in both capsules were effectively released.
7. Stability Testing (Brittleness and Loss on Drying):
• Brittleness Testing: Both the single capsule formulation and the CiC formulation were subjected to brittleness testing to evaluate their mechanical integrity under conditions mimicking real-world handling.
o Single Capsule (Blend): 00/40 (No breakage).
o CiC System: 2/80 (Minor breakage of the outer capsule, but no impact on performance).
• Loss on Drying (LOD): Both formulations showed similar moisture content, indicating comparable stability.
o Single Capsule: Initial LOD = 14.21%.
o CiC System: Initial LOD = 14.26%.
Conclusion: The Capsule-in-Capsule (CiC) system for the co-delivery of Levosalbutamol and Ipratropium demonstrated comparable performance to the single capsule formulation in terms of Fine Particle Dose (FPD) and Percent Dose Delivery (PDD). Additionally, the CiC system has potential to prevent direct contact between the active ingredients, which may enhance the stability of the formulation and decrease the impurity generation. The puncturing performance, brittleness, and moisture content results further confirm the viability of the capsule-in-capsule system for use in Dry Powder Inhalers (DPI).
[00055] While the foregoing description discloses various embodiments of the disclosure, other and further embodiments of the invention may be devised without departing from the basic scope of the disclosure.
,CLAIMS:1.) A capsules based dry powder inhaler (DPI) system comprising:
? a first capsule containing a first pharmaceutical formulation, said formulation comprising a first active pharmaceutical ingredient (API) and at least one excipient for stabilizing the API; and
? a second capsule contained within said first capsule, said second capsule containing a second pharmaceutical formulation comprising a second API and at least one excipient for stabilizing the second API, wherein said first API and said second API are housed in separate capsules to prevent direct contact with each other until the capsules are ruptured by an inhalation device.
2.) The dry powder inhaler system as claimed in claim 1, wherein said first API is a corticosteroid selected from the group consisting of Budesonide, Fluticasone Propionate, Beclomethasone Dipropionate, and Levosalbutamol sulfate, and said second API is a bronchodilator selected from the group consisting of Formoterol Fumarate, Salmeterol, Levosalbutamol, and Ipratropium Bromide.
3.) The dry powder inhaler system as claimed in claim 1, wherein said excipients in said first and second capsules include carriers, lubricants, and stabilizers to ensure stability, flowability, and aerosolization of said dry powder formulation.
4.) The dry powder inhaler system as claimed in claim 1, wherein said first and second capsules are structurally isolated from each other to prevent physical contact until the point of inhalation, and rupture of the capsules is triggered by an external inhalation device upon activation.
5.) The dry powder inhaler system as claimed in claim 1, wherein the inhalation device includes a mechanical piercing mechanism that causes effective rupture of the first and second capsule in a simultaneous manner to allow for the release of the respective APIs.
6.) The dry powder inhaler system as claimed in claim 1, wherein said first and second capsule are made from a material selected from the group consisting of gelatin, hydroxypropyl methylcellulose (HPMC), and pullulan.
7.) The dry powder inhaler system as claimed in claim 1, wherein said excipients are pharmaceutically acceptable excipients selected from the group consisting of microcrystalline cellulose, lactose, mannitol, polyvinylpyrrolidone and magnesium sterate.

8.) A pharmaceutical formulation for a dry powder inhaler, comprising:
? a first active pharmaceutical ingredient (API) formulated in a first dry powder formulation, and
? a second active pharmaceutical ingredient (API) formulated in a second dry powder formulation; wherein said first formulation and said second formulation are separated into distinct capsules within a capsule-in-capsule (CiC) system, and the APIs are released in a effective manner upon inhalation.

9.) The pharmaceutical formulation as claimed in claim 8, wherein said first API is a corticosteroid, and said second API is a bronchodilator.
10.) The pharmaceutical formulation as claimed in claim 8, wherein said excipients include carriers, lubricants, stabilizer selected to maintain the stability and flowability of the powder and facilitate its dispersion during inhalation.
11.) The pharmaceutical formulation as claimed in claim 8, wherein the release rate of said first and second APIs is designed to mimic the biopharmaceutical properties required for effective lung deposition and therapeutic efficacy.