WO2023224577A1 - Inhalation compositions comprising micronized human insulin - Google Patents

Inhalation compositions comprising micronized human insulin Download PDF

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Publication number
WO2023224577A1
WO2023224577A1 PCT/TR2022/050445 TR2022050445W WO2023224577A1 WO 2023224577 A1 WO2023224577 A1 WO 2023224577A1 TR 2022050445 W TR2022050445 W TR 2022050445W WO 2023224577 A1 WO2023224577 A1 WO 2023224577A1
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WO
WIPO (PCT)
Prior art keywords
dry powder
lactose
inhalation
composition
powder composition
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Application number
PCT/TR2022/050445
Other languages
French (fr)
Inventor
Devrim CELIK SAKIZCI
Turgay KACAR
Ali Ihsan SECKIN
Emine Yilmaz
Original Assignee
Arven Ilac Sanayi Ve Ticaret Anonim Sirketi
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Application filed by Arven Ilac Sanayi Ve Ticaret Anonim Sirketi filed Critical Arven Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority to PCT/TR2022/050445 priority Critical patent/WO2023224577A1/en
Publication of WO2023224577A1 publication Critical patent/WO2023224577A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules

Definitions

  • the invention relates to dry powder pharmaceutical compositions for use in a dry powder inhaler for the treatment of types I and II diabetes in mammalians, particularly in humans comprising micronized human insulin as an active agent and at least one pharmaceutically acceptable excipient. Further, the present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process.
  • Diabetes mellitus is a group of disorders of carbohydrate metabolism in which the action of insulin is diminished or absent through altered secretion, decreased insulin activity or a combination of both factors.
  • Type 1 and Type 2 There are two main types of diabetes; Type 1 and Type 2:
  • Type 1 diabetes occurs because the insulin-producing cells of the pancreas (beta cells) are damaged. In Type 1 diabetes, the pancreas produces little or no insulin, so sugar cannot get into the body's cells for use as energy.
  • pancreas In Type 2 diabetes, the pancreas produces insulin, but it either doesn't produce enough or the insulin does not work properly.
  • the goal of diabetes treatment is to keep blood glucose levels as close to normal as safely possible.
  • the purpose of these treatments is that improve the effectiveness of the body's natural insulin, reduce blood sugar production, increase insulin production and inhibit blood sugar absorption.
  • Insulin analogs are analogs that have been designed to mimic the body’s natural pattern of insulin release. These synthetic-made insulins are called analogs of human insulin. However, they have minor structural or amino acid changes. Once absorbed, they act on cells like human insulin, but are absorbed from fatty tissue more predictably and the duration of action of these insulin analogs may be shorter. The activity of insulin analogs is not well synchronized with your body’s needs.
  • Human insulin consists of two polypeptide chains, the A and B chains which contain 21 and 30 amino acid residues.
  • the A and B chains are interconnected by two disulfide bridges. Insulin from most other species is similar but may contain amino acid substitutions in some positions.
  • Human insulin is marketed under the brand name Huminsulin® R by Eli Lilly is a biphasic isophane insulin injection. It comprises soluble insulin, isophane insulin and pharmaceutical acceptable excipients which are preservative, tonicity modifier, pH adjustment agent. Also, other medicinal product Mixtard® marketed by Novo Nordisk is a dual-acting, biphasic formulation comprises a premix of soluble fast-acting insulin human, isophane long-acting insulin and at least one pharmaceutical acceptable excipients.
  • Human insulin is identical in structure to our own natural insulin. But when it is injected under the skin it doesn’t work as well as natural insulin. This is because injected subcutaneously human insulin clumps together and takes a long time to get absorbed.
  • Inhaled insulin passes through the lungs and directly into the bloodstream and it is known that the bioavailability of inhaled insulin is higher than subcutaneous administration.
  • the inhaled human insulin product is marketed under the brand name Afrezza® by MannKind Corporation, was approved by the FDA in 2014.
  • Afrezza powder for inhalation is available as single-use 4 III, 8 III, and 12 IU cartridges.
  • Dry powder pharmaceutical compositions that are suitable to be used via dry powder inhaler (DPI) must fulfill a number of demands. With the aim of fulfilling these demands, it would be highly advantageous to provide a formulation exhibiting good uniformity of distribution of the active ingredient, small drug dosage variation (in other words, adequate accuracy of the delivered doses), good flowability, adequate physical stability in the device before use.
  • DPI dry powder inhaler
  • the performance of a dry powder inhaler also depends on the formulation delivered to the lungs using this device besides the inhaler characteristics.
  • Formulations which are delivered via dry powder inhalers are in dry powder form and have an improved stability, an easier use and a more efficient drug delivery as compared to those formulations delivered using injection.
  • the size of the drug particles in a formulation administered via dry powder inhalers is closely related to the influence of the respective drug.
  • dry powder formulations prepared for inhalation therapy are formulated using drug particles of a micronized size.
  • the particle size has to be below 5 pm for the absorption of the drug particles to occur at the target sites. Particles of this size are also known as "inhalable particles". Since drug particles of a size above 5 pm are mostly accumulated in the oropharyngeal cavity, the target sites cannot be reached and therefore the desired therapeutic effect cannot be obtained.
  • the drugs used in inhalation therapy have a quite strong effect and the dose of a drug to be delivered to achieve a therapeutic benefit per inhalation is in the unit of micrograms. For this reason, it is quite difficult to portion a drug into the capsules, blister cavities or reservoirs under high accuracy and precision. Therefore, drug particles used in inhalation therapy are diluted using suitable carrier particles. Since the amount of carrier particles used for diluting the micronized drug particles is substantially high, the type of these carrier particles and the particle size distribution thereof significantly influences the properties such as flowability of the dry powder formulation. Therefore, it has been found to be very important to use the fine (small) and coarse (large) particles of the selected carrier in the formulations of the present invention in an accurate ratio.
  • DPI formulations should be adapted especially by carefully choosing the employed carriers.
  • the inhalable, fine or micro-fine particles of the active compounds are mixed with carriers.
  • the particle size of the carrier can be changed in order that a certain amount thereof to become inhalable.
  • the particle size of the employed carrier depends on the requirements and specifications of the powder inhaler used for the application of the formulation.
  • an inhalation composition comprising micronized human insulin is provided. Also, an inhalation composition has been developed by using standard techniques which is a simple, time-saving and cost-effective method.
  • Present invention relates to a dry powder composition for use in a dry powder inhaler comprising micronized human insulin overcoming all the aforementioned problems and bringing further advantages to the technical field.
  • Main object of the present invention is to obtain an effective and stable inhalation composition comprising micronized human insulin.
  • Another object of the present invention is to obtain inhalation compositions comprising pharmaceutically acceptable surfactant for ensuring fluidity.
  • Another object of the present invention is to obtain inhalation compositions having appropriate active agent particle size range ensuring that effective doses of active agents reach the alveoli.
  • a further object of the present invention is to obtain inhalation compositions which can be filled in blister or in capsule which is applicable with an inhaler.
  • a further object of the present invention is to obtain a blister filled with the above-mentioned inhalation compositions.
  • a further object of the present invention is to obtain capsules filled with the above-mentioned inhalation compositions.
  • a further object of the present invention is to obtain an inhaler which is useable with the above- mentioned blister or the above-mentioned capsules.
  • a further object of the present invention is to obtain an inhaler that ensures accurate, reproducible and safe delivery of insulin to the patient.
  • a further object of the present invention to obtain a process which is used for preparing the homogeneous dry powder formulation with high content uniformity that enables high dose reproducibility to be achieved.
  • Another object of the present invention is to obtain a therapeutically effective product without degradation.
  • the present invention relates to a dry powder composition for inhalation comprising: micronized human insulin,
  • the amount of micronized human insulin is between 0.1 - 50%, preferably 0.1 -47%, more preferably 0.1 -45% by weight of the total composition.
  • the micronized human insulin has a D 5 o particle size is between 0.1 -50pm, preferably 0.5-20pm, more preferably 1-10pm.
  • the inhalation composition comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising carriers, surfactants or mixtures thereof.
  • the carrier is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol, maltitol or mixtures thereof to provide fluidity and to ensure that the active ingredients accurately and consistently reach the lungs.
  • said carrier is lactose, more preferably lactose monohydrate.
  • said lactose comprises coarse lactose and fine lactose.
  • the type of the fine carrier can be the same as or different from the type of the coarse carrier.
  • the fine carrier and coarse carrier may constitute a combination of lactose and lactose, mannitol and glucose, or mannitol and trehalose, or mannitol and sorbitol, or mannitol and cellobiose, or mannitol and maltitol, or lactose and mannitol, or lactose and glucose, or lactose and trehalose, or lactose and sorbitol, or lactose and cellobiose, lactose and maltitol.
  • lactose is preferably used as both of the fine carrier and the coarse carrier.
  • lactose is lactose monohydrate.
  • the amount of the fine lactose is in the range of 0- 30%, preferably 0.5-20%, more preferably 1 -15% by weight of the total composition.
  • the amount of total lactose is between 50-99.9%, preferably 53-99.9%, more preferably 55-99.9 % by weight of the total composition.
  • said lactose monohydrate comprises coarse lactose of which the mean particle size is between 25-300 pm, preferably 35-250 pm and said lactose monohydrate comprises fine lactose of which the mean particle size is between 0.01 - 25 pm, preferably 0.01-20 pm.
  • “Mean particle size” represents the D 5 o value of the particles which is measured by the laser diffraction method.
  • Laser diffraction measures particle size distributions by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating the scattering. The particle size is reported as a volume equivalent sphere diameter.
  • Coarse carrier particles are used to prevent agglomeration of the active agent particles having mean particle size lower than 10 pm.
  • shape and surface roughness of the carrier particles are especially important. Particles having smooth surface will be separated much easier from the active agents compared to the particles in the same size but having high porosity.
  • Active agent particles will tend to concentrate on the regions having higher energy as the surface energy does not dissipate on the coarse carrier particles evenly. This might prevent separation of the active agent particles from the coarse carrier after pulmonary administration, especially in low dose formulations.
  • fine carrier particles are used to help the active agents to reach to the lungs easier and in high doses. As the high-energy regions of coarse carrier particles will be covered by fine carrier particles, the active agent particles will be attaching to low energy regions; thus, the amount of active agent particles detached from the coarse carrier particles will potentially increase.
  • the drug particles In order to get drug delivery into the lungs from a DPI formulation, the drug particles have to detach from surface of the carrier particles and penetrate into the lungs.
  • the adhesive and cohesive forces between contiguous particle surfaces affect the detachment of the drug particles from surface of the carrier particles, and thus aerosolization of respirable particles in dry powder formulation.
  • the different surface properties of the carrier resulted in different adhesive forces between the drug and the carrier, which was reflected in the lung deposition results.
  • the adhesive forces that exist between drug and carrier particles have to be overcome in order to aerosolize drug particles.
  • the magnitude of the attachment forces during inhalation relative to the adhesive forces in the mixture determines the obtained fine particle fraction (FPF).
  • the dry powder composition further comprises at least one additive, the additive is selected from amino acids (glycine, leucine, lysine, valine, methionine, phenylalanine alanine, isoleucine, tryptophane).
  • the additive is selected from amino acids (glycine, leucine, lysine, valine, methionine, phenylalanine alanine, isoleucine, tryptophane).
  • the surfactant is selected from the group comprising magnesium stearate, sodium stearate or mixtures thereof.
  • the amount of surfactant is in the range of 0-1 .5%, preferably 0.05-1 .4%, more preferably 0.1 -1 .3 % by weight of the total composition.
  • the surfactant is preferably used for the above-mentioned purpose in dry powder formulations.
  • some of the active sites of carrier particles are occupied by the surfactant and the inter particulate forces (i.e. adhesive forces and cohesive forces) are balanced in the formulation, therefore not being too weak which would lead to the falling off the drug particles and forming agglomerates and not too strong which would not enable their detachment from the carrier surface.
  • the surfactant only some of the active sites are occupied by the surfactant, enabling some active sites to be occupied by the drug particles and therefore aerosolize upon actuation.
  • Moisture uptake can directly affect the flowability of the powders and the force to detach the micronized particles from the carrier surface.
  • Use for magnesium stearate in the formulation of the present invention also helps to minimize the influence of penetrating moisture during the storage of said formulation and results in said formulation to be more stable against the moisture.
  • the quality of the pharmaceutical formulation remains considerably better than conventional formulations which are free of magnesium stearate even on storage under extreme conditions of temperature and humidity. Therefore, the use of magnesium stearate also improves the moisture resistance of the dry powder formulations.
  • the above-mentioned surfactants are poorly water-soluble, its presence in such amount may raise some concerns as to a potential irritation or toxicity of this excipient, part of which can be inhaled by the patient together with the active ingredient. Therefore, it is important to determine the optimum concentration of surfactant that enables eliminating or minimizing potential irritation or toxicity of this excipient while getting balanced inter particulate forces between the human insulin particles and the carrier surface which will enable maximum aerosolization deposition and minimizing the influence of penetrating moisture during the storage of the formulation.
  • the dry powder composition for inhalation is formulated to comprise micronized human insulin, a pharmaceutically acceptable carrier and surfactant, the adhesive and cohesive forces between micronized human insulin and the pharmaceutically acceptable carrier particles are well-balanced and the dry powder formulation that exhibits good uniformity of distribution of micronized human insulin, small drug dosage variation (in other words, adequate accuracy of the delivered doses), good flowability, adequate stability in the device before use, good aerosolization performance in terms of emitted dose and fine particle fraction (FPF) is provided.
  • small drug dosage variation in other words, adequate accuracy of the delivered doses
  • good flowability adequate stability in the device before use
  • good aerosolization performance in terms of emitted dose and fine particle fraction (FPF) is provided.
  • lactose is a slightly hygroscopic carrier, it enhances stability and it does not cause agglomeration, thus facilitates the filling process of the composition into the blister or into the capsule.
  • the inhalation composition subjected to the invention comprises;
  • Example 1 Inhalation composition 1
  • Example 3 Inhalation composition 3
  • Example 4 Inhalation composition 4
  • Example 5 Inhalation composition 5 A process for the preparation of the dry powder composition for inhalation comprises the following steps:
  • the dry powder pharmaceutical composition of micronized human insulin in accordance with this invention can be prepared using the above method which is a simple and low-cost production method was employed.
  • Micronized human insulin and pharmaceutically acceptable carrier and surfactant can be mixed using any suitable blending apparatus which is selected from the high shear mixer (for example a QMM, PMA or TRV series mixer) or a low shear tumbling mixer (a Turbula mixer).
  • a suitable blending apparatus which is selected from the high shear mixer (for example a QMM, PMA or TRV series mixer) or a low shear tumbling mixer (a Turbula mixer).
  • the process for the preparation of the dry powder composition for inhalation is carried out with a high shear mixer.
  • said mixer further comprises a chopper with a rotation speed of 0-3000 rpm, preferably 0-2000 rpm, more preferably 0-1500 rpm.
  • said mixer further comprises a impeller with a rotation speed of 0-800 rpm, preferably 0-600 rpm, more preferably 0-500 rpm.
  • the dry powder composition subjected to the invention is suitable for administration in dosage forms such as capsules or blister packs.
  • the inhalation composition is presented in blisters.
  • the inhalation composition is suitable for administration in a multi-dose system, more preferably in a multi-dose blister pack which has more than one blister with air and moisture barrier property.
  • the said blister pack comprises an aluminum material covering them to prevent moisture intake.
  • Each blister is further encapsulated with a material resistant to moisture. By this means, blisters prevent water penetration and moisture intake from outside into the composition.
  • Each blister contains the same amount of active agent and carrier which is provided via content uniformity and dosage accuracy of the composition. For this invention, it is ensured by the specific selection of carrier, its amount and mean particle sizes.
  • a single blister (a single dose) contains 3-13 mg inhalation composition subjected to the invention.
  • a single capsule (a single dose) contains 3-25 mg inhalation composition subjected to the invention.
  • the said blister pack is arranged to be loaded in a dry powder inhaler and the composition is configured to be delivered to the lungs via the said inhaler.
  • the inhaler has means to open the blister and to provide respective delivery of each unit dose.
  • the said inhaler further comprises a lid and a lock mechanism connected to the lid which is arranged to maintain the inhaler locked in both positions in which it is ready for inhalation and the lid is closed.
  • the inhaler also ensures to be automatically re-set once the lid is closed.
  • inhalation composition subjected to the invention is used for the treatment of types I and II diabetes in mammalians, particularly in humans.

Abstract

The invention relates to dry powder pharmaceutical compositions for use in a dry powder inhaler for the treatment of types I and II diabetes in mammalians, particularly in humans comprising micronized human insulin as an active agent and at least one pharmaceutically acceptable excipient. Further, the present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process.

Description

INHALATION COMPOSITIONS COMPRISING MICRONIZED HUMAN INSULIN
Technical Field
The invention relates to dry powder pharmaceutical compositions for use in a dry powder inhaler for the treatment of types I and II diabetes in mammalians, particularly in humans comprising micronized human insulin as an active agent and at least one pharmaceutically acceptable excipient. Further, the present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process.
Background of the Invention
Diabetes mellitus is a group of disorders of carbohydrate metabolism in which the action of insulin is diminished or absent through altered secretion, decreased insulin activity or a combination of both factors. There are two main types of diabetes; Type 1 and Type 2:
Type 1 diabetes occurs because the insulin-producing cells of the pancreas (beta cells) are damaged. In Type 1 diabetes, the pancreas produces little or no insulin, so sugar cannot get into the body's cells for use as energy.
In Type 2 diabetes, the pancreas produces insulin, but it either doesn't produce enough or the insulin does not work properly.
The goal of diabetes treatment is to keep blood glucose levels as close to normal as safely possible. There are several different ways for treatment of diabetes. The most common of these are insulin (human insulin and insulin analogs) or adjuvant (non-insulin) subcutaneous or oral antidiabetic formulation. The purpose of these treatments is that improve the effectiveness of the body's natural insulin, reduce blood sugar production, increase insulin production and inhibit blood sugar absorption.
However, the use of these adjuvant (non-insulin) subcutaneous or oral antidiabetic formulation is associated with various adverse effects, especially have side effects that are dependent on the excipient used.
Human insulin and insulin analogues are preferred and used by most adults with type 1 diabetes. Insulin analogs are analogs that have been designed to mimic the body’s natural pattern of insulin release. These synthetic-made insulins are called analogs of human insulin. However, they have minor structural or amino acid changes. Once absorbed, they act on cells like human insulin, but are absorbed from fatty tissue more predictably and the duration of action of these insulin analogs may be shorter. The activity of insulin analogs is not well synchronized with your body’s needs.
Human insulin consists of two polypeptide chains, the A and B chains which contain 21 and 30 amino acid residues. The A and B chains are interconnected by two disulfide bridges. Insulin from most other species is similar but may contain amino acid substitutions in some positions.
Human insulin is marketed under the brand name Huminsulin® R by Eli Lilly is a biphasic isophane insulin injection. It comprises soluble insulin, isophane insulin and pharmaceutical acceptable excipients which are preservative, tonicity modifier, pH adjustment agent. Also, other medicinal product Mixtard® marketed by Novo Nordisk is a dual-acting, biphasic formulation comprises a premix of soluble fast-acting insulin human, isophane long-acting insulin and at least one pharmaceutical acceptable excipients.
Human insulin is identical in structure to our own natural insulin. But when it is injected under the skin it doesn’t work as well as natural insulin. This is because injected subcutaneously human insulin clumps together and takes a long time to get absorbed.
Inhaled insulin passes through the lungs and directly into the bloodstream and it is known that the bioavailability of inhaled insulin is higher than subcutaneous administration.
The inhaled human insulin product is marketed under the brand name Afrezza® by MannKind Corporation, was approved by the FDA in 2014. Afrezza powder for inhalation is available as single-use 4 III, 8 III, and 12 IU cartridges.
Dry powder pharmaceutical compositions, that are suitable to be used via dry powder inhaler (DPI), must fulfill a number of demands. With the aim of fulfilling these demands, it would be highly advantageous to provide a formulation exhibiting good uniformity of distribution of the active ingredient, small drug dosage variation (in other words, adequate accuracy of the delivered doses), good flowability, adequate physical stability in the device before use.
The performance of a dry powder inhaler also depends on the formulation delivered to the lungs using this device besides the inhaler characteristics. Formulations which are delivered via dry powder inhalers are in dry powder form and have an improved stability, an easier use and a more efficient drug delivery as compared to those formulations delivered using injection.
In inhalation therapy, the size of the drug particles in a formulation administered via dry powder inhalers is closely related to the influence of the respective drug. In order to gain a therapeutic benefit from the inhaled drug particles, they have to be absorbed in the lungs, i.e. at the bronchial and alveolar sites. For this reason, dry powder formulations prepared for inhalation therapy are formulated using drug particles of a micronized size. The particle size has to be below 5 pm for the absorption of the drug particles to occur at the target sites. Particles of this size are also known as "inhalable particles". Since drug particles of a size above 5 pm are mostly accumulated in the oropharyngeal cavity, the target sites cannot be reached and therefore the desired therapeutic effect cannot be obtained.
It is a pre-condition for the medicament to possess content uniformity, in terms of user safety and effectiveness of the treatment. The difference of the particle sizes between the carrier used is important in order to ensure content uniformity. This difference to be beyond measure prevents to achieve the desired content uniformity. Another potential problem is to be unable to achieve the dosage accuracy present in each cavity in the blister or capsule. And this is of vital importance in terms of the effectiveness of the treatment.
Since the cohesion forces between micronized particles are too high, they tend to agglomerate and thus have weak flow properties. In order to develop a successful product and achieve an efficient inhalation, it is quite important to adjust and control the flow properties of the particles in the formulation. Mixing the cohesive particles during production is very problematic, and additionally, it is necessary to fill the dry powder formulations prepared into the blister cavities, capsules or reservoirs used in dry powder inhalers with high dose accuracy. Further, the flowability of dry powder formulations also affects the drug performance by influencing some factors such as discharging a dose from the inhaler and aerosolizing the particles into inhalable particles during inhalation.
Having said that, the drugs used in inhalation therapy have a quite strong effect and the dose of a drug to be delivered to achieve a therapeutic benefit per inhalation is in the unit of micrograms. For this reason, it is quite difficult to portion a drug into the capsules, blister cavities or reservoirs under high accuracy and precision. Therefore, drug particles used in inhalation therapy are diluted using suitable carrier particles. Since the amount of carrier particles used for diluting the micronized drug particles is substantially high, the type of these carrier particles and the particle size distribution thereof significantly influences the properties such as flowability of the dry powder formulation. Therefore, it has been found to be very important to use the fine (small) and coarse (large) particles of the selected carrier in the formulations of the present invention in an accurate ratio.
In order to meet all these requirements, DPI formulations should be adapted especially by carefully choosing the employed carriers. In order to meet these requirements, the inhalable, fine or micro-fine particles of the active compounds are mixed with carriers. By means of the mixing process, the particle size of the carrier can be changed in order that a certain amount thereof to become inhalable. The particle size of the employed carrier depends on the requirements and specifications of the powder inhaler used for the application of the formulation.
Thus, there is still a need for a dry powder composition of micronized human insulin for inhalation, which provides high stability and at the same time ensures fluidity, content uniformity and dosage accuracy.
In this invention, to overcome these problems mentioned above, an inhalation composition comprising micronized human insulin is provided. Also, an inhalation composition has been developed by using standard techniques which is a simple, time-saving and cost-effective method.
Objects and Brief Description of the Invention
In accordance with the objects outlined above, detailed features of the present invention are given herein.
Present invention relates to a dry powder composition for use in a dry powder inhaler comprising micronized human insulin overcoming all the aforementioned problems and bringing further advantages to the technical field.
Main object of the present invention is to obtain an effective and stable inhalation composition comprising micronized human insulin.
Another object of the present invention is to provide a dry powder composition with improved flow properties for use in the treatment of types I and II diabetes in mammalians, particularly in humans. Another object of the present invention is to obtain inhalation compositions comprising two different types of pharmaceutically acceptable carriers in terms of particle size.
Another object of the present invention is to obtain inhalation compositions comprising pharmaceutically acceptable surfactant for ensuring fluidity.
Another object of the present invention is to obtain inhalation compositions having appropriate active agent particle size range ensuring that effective doses of active agents reach the alveoli.
A further object of the present invention is to obtain inhalation compositions which can be filled in blister or in capsule which is applicable with an inhaler.
A further object of the present invention is to obtain a blister filled with the above-mentioned inhalation compositions.
A further object of the present invention is to obtain capsules filled with the above-mentioned inhalation compositions.
A further object of the present invention is to obtain an inhaler which is useable with the above- mentioned blister or the above-mentioned capsules.
A further object of the present invention is to obtain an inhaler that ensures accurate, reproducible and safe delivery of insulin to the patient.
A further object of the present invention to obtain a process which is used for preparing the homogeneous dry powder formulation with high content uniformity that enables high dose reproducibility to be achieved.
Another object of the present invention is to obtain a therapeutically effective product without degradation.
Detailed Description of Invention
In accordance with the objects outlined above, detailed features of the present invention are given herein.
The present invention relates to a dry powder composition for inhalation comprising: micronized human insulin,
- at least one pharmaceutically acceptable carrier, and
- at least one pharmaceutically acceptable surfactant
According to the one embodiment, the amount of micronized human insulin is between 0.1 - 50%, preferably 0.1 -47%, more preferably 0.1 -45% by weight of the total composition.
According to the preferred embodiment, the micronized human insulin has a D5o particle size is between 0.1 -50pm, preferably 0.5-20pm, more preferably 1-10pm.
According to the one embodiment, the inhalation composition comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising carriers, surfactants or mixtures thereof.
In a preferred embodiment, the carrier is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol, maltitol or mixtures thereof to provide fluidity and to ensure that the active ingredients accurately and consistently reach the lungs.
According to the preferred embodiment, said carrier is lactose, more preferably lactose monohydrate. And said lactose comprises coarse lactose and fine lactose. Additionally, the type of the fine carrier can be the same as or different from the type of the coarse carrier. The fine carrier and coarse carrier may constitute a combination of lactose and lactose, mannitol and glucose, or mannitol and trehalose, or mannitol and sorbitol, or mannitol and cellobiose, or mannitol and maltitol, or lactose and mannitol, or lactose and glucose, or lactose and trehalose, or lactose and sorbitol, or lactose and cellobiose, lactose and maltitol. According to present invention, lactose is preferably used as both of the fine carrier and the coarse carrier.
In one embodiment of the present invention, lactose is lactose monohydrate.
According to this preferred embodiment, the amount of the fine lactose is in the range of 0- 30%, preferably 0.5-20%, more preferably 1 -15% by weight of the total composition.
According to one embodiment, the amount of total lactose is between 50-99.9%, preferably 53-99.9%, more preferably 55-99.9 % by weight of the total composition.
According to the most preferred embodiment, said lactose monohydrate comprises coarse lactose of which the mean particle size is between 25-300 pm, preferably 35-250 pm and said lactose monohydrate comprises fine lactose of which the mean particle size is between 0.01 - 25 pm, preferably 0.01-20 pm.
“Mean particle size” represents the D5o value of the particles which is measured by the laser diffraction method. Laser diffraction measures particle size distributions by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating the scattering. The particle size is reported as a volume equivalent sphere diameter.
Coarse carrier particles are used to prevent agglomeration of the active agent particles having mean particle size lower than 10 pm. During inhalation, as the active agent and the carrier particles need to be separated from each other, shape and surface roughness of the carrier particles are especially important. Particles having smooth surface will be separated much easier from the active agents compared to the particles in the same size but having high porosity.
Active agent particles will tend to concentrate on the regions having higher energy as the surface energy does not dissipate on the coarse carrier particles evenly. This might prevent separation of the active agent particles from the coarse carrier after pulmonary administration, especially in low dose formulations. In this regard, fine carrier particles are used to help the active agents to reach to the lungs easier and in high doses. As the high-energy regions of coarse carrier particles will be covered by fine carrier particles, the active agent particles will be attaching to low energy regions; thus, the amount of active agent particles detached from the coarse carrier particles will potentially increase.
In order to get drug delivery into the lungs from a DPI formulation, the drug particles have to detach from surface of the carrier particles and penetrate into the lungs. The adhesive and cohesive forces between contiguous particle surfaces affect the detachment of the drug particles from surface of the carrier particles, and thus aerosolization of respirable particles in dry powder formulation. The different surface properties of the carrier resulted in different adhesive forces between the drug and the carrier, which was reflected in the lung deposition results. During inhalation, the adhesive forces that exist between drug and carrier particles have to be overcome in order to aerosolize drug particles. The magnitude of the attachment forces during inhalation relative to the adhesive forces in the mixture determines the obtained fine particle fraction (FPF). Consequently, optimizing a dry powder inhalation system with respect to delivered fine particle dose requires careful balancing between both types of forces. The attachment forces have to be strong enough to maintain satisfactory blend homogeneity during handling, storage and transportation but weak enough to yield a high drug release from the carrier particles during inhalation.
It has been seen that these particle size ranges ensure effective doses of active agents reaching the alveoli.
According to another embodiment of the present invention, the dry powder composition further comprises at least one additive, the additive is selected from amino acids (glycine, leucine, lysine, valine, methionine, phenylalanine alanine, isoleucine, tryptophane).
In a preferred embodiment, the surfactant is selected from the group comprising magnesium stearate, sodium stearate or mixtures thereof.
According to this preferred embodiment, the amount of surfactant is in the range of 0-1 .5%, preferably 0.05-1 .4%, more preferably 0.1 -1 .3 % by weight of the total composition.
The surfactant is preferably used for the above-mentioned purpose in dry powder formulations. When surfactant is used in the dry powder formulations, some of the active sites of carrier particles are occupied by the surfactant and the inter particulate forces (i.e. adhesive forces and cohesive forces) are balanced in the formulation, therefore not being too weak which would lead to the falling off the drug particles and forming agglomerates and not too strong which would not enable their detachment from the carrier surface. However, only some of the active sites are occupied by the surfactant, enabling some active sites to be occupied by the drug particles and therefore aerosolize upon actuation.
Moisture uptake can directly affect the flowability of the powders and the force to detach the micronized particles from the carrier surface. Use for magnesium stearate in the formulation of the present invention also helps to minimize the influence of penetrating moisture during the storage of said formulation and results in said formulation to be more stable against the moisture. Thus, the quality of the pharmaceutical formulation remains considerably better than conventional formulations which are free of magnesium stearate even on storage under extreme conditions of temperature and humidity. Therefore, the use of magnesium stearate also improves the moisture resistance of the dry powder formulations. However, the above-mentioned surfactants are poorly water-soluble, its presence in such amount may raise some concerns as to a potential irritation or toxicity of this excipient, part of which can be inhaled by the patient together with the active ingredient. Therefore, it is important to determine the optimum concentration of surfactant that enables eliminating or minimizing potential irritation or toxicity of this excipient while getting balanced inter particulate forces between the human insulin particles and the carrier surface which will enable maximum aerosolization deposition and minimizing the influence of penetrating moisture during the storage of the formulation.
It has been surprisingly found that when the dry powder composition for inhalation is formulated to comprise micronized human insulin, a pharmaceutically acceptable carrier and surfactant, the adhesive and cohesive forces between micronized human insulin and the pharmaceutically acceptable carrier particles are well-balanced and the dry powder formulation that exhibits good uniformity of distribution of micronized human insulin, small drug dosage variation (in other words, adequate accuracy of the delivered doses), good flowability, adequate stability in the device before use, good aerosolization performance in terms of emitted dose and fine particle fraction (FPF) is provided.
Since lactose is a slightly hygroscopic carrier, it enhances stability and it does not cause agglomeration, thus facilitates the filling process of the composition into the blister or into the capsule.
According to one preferred embodiment, the inhalation composition subjected to the invention comprises;
- 0.1 -50% by weight of micronized human insulin
- 0-40% by weight of fine lactose
- 99.9-50 % by weight of total lactose
The following non-limiting examples further illustrate the invention. According to all these embodiments, the below given formulations can be used for the inhalation composition subjected to the invention. Example 1 : Inhalation composition 1
Figure imgf000011_0001
Example 2: Inhalation composition 2
Figure imgf000011_0002
Example 3: Inhalation composition 3
Figure imgf000011_0003
Example 4: Inhalation composition 4
Figure imgf000011_0004
Example 5: Inhalation composition 5
Figure imgf000011_0005
A process for the preparation of the dry powder composition for inhalation comprises the following steps:
- plastering the inner wall of a container with %50 by weight of coarse lactose,
- adding fine lactose and micronized human insulin into the plastered container and mixing,
- adding %50 by weight of coarse lactose and mixing,
- adding surfactant and obtaining the final powder, filling the final powder mixture into blisters or capsules.
According to one embodiment of the present invention, the dry powder pharmaceutical composition of micronized human insulin in accordance with this invention can be prepared using the above method which is a simple and low-cost production method was employed.
Micronized human insulin and pharmaceutically acceptable carrier and surfactant can be mixed using any suitable blending apparatus which is selected from the high shear mixer (for example a QMM, PMA or TRV series mixer) or a low shear tumbling mixer (a Turbula mixer).
According to one embodiment of the present invention, the process for the preparation of the dry powder composition for inhalation is carried out with a high shear mixer.
According to one embodiment, said mixer further comprises a chopper with a rotation speed of 0-3000 rpm, preferably 0-2000 rpm, more preferably 0-1500 rpm.
According to one embodiment, said mixer further comprises a impeller with a rotation speed of 0-800 rpm, preferably 0-600 rpm, more preferably 0-500 rpm.
The dry powder composition subjected to the invention is suitable for administration in dosage forms such as capsules or blister packs.
According to an embodiment, the inhalation composition is presented in blisters.
According to an embodiment, the inhalation composition is suitable for administration in a multi-dose system, more preferably in a multi-dose blister pack which has more than one blister with air and moisture barrier property. The said blister pack comprises an aluminum material covering them to prevent moisture intake. Each blister is further encapsulated with a material resistant to moisture. By this means, blisters prevent water penetration and moisture intake from outside into the composition. Each blister contains the same amount of active agent and carrier which is provided via content uniformity and dosage accuracy of the composition. For this invention, it is ensured by the specific selection of carrier, its amount and mean particle sizes.
In a preferred embodiment, a single blister (a single dose) contains 3-13 mg inhalation composition subjected to the invention.
In a preferred embodiment, a single capsule (a single dose) contains 3-25 mg inhalation composition subjected to the invention.
In the most preferred embodiment, the said blister pack is arranged to be loaded in a dry powder inhaler and the composition is configured to be delivered to the lungs via the said inhaler. The inhaler has means to open the blister and to provide respective delivery of each unit dose.
In a preferred embodiment, the said inhaler further comprises a lid and a lock mechanism connected to the lid which is arranged to maintain the inhaler locked in both positions in which it is ready for inhalation and the lid is closed. According to this embodiment, the inhaler also ensures to be automatically re-set once the lid is closed.
According to a preferred embodiment, inhalation composition subjected to the invention is used for the treatment of types I and II diabetes in mammalians, particularly in humans.

Claims

1. A dry powder composition for inhalation comprising: micronized human insulin, at least one pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable surfactant
2. The dry powder composition for inhalation according to claim 1, wherein the amount of micronized human insulin is between 0.1-50%, preferably 0.1-47%, more preferably 0.1- 45% by weight of the total composition.
3. The dry powder composition for inhalation according to to claim 1 , wherein said micronized human insulin has a D50 particle size is between 0.1 -50pm, preferably 0.5-20pm, more preferably 1-10pm.
4. The dry powder composition for inhalation according to claim 1 , wherein the pharmaceutically acceptable carrier is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol, maltitol or mixtures thereof.
5. The dry powder composition for inhalation according to claim 4, wherein the pharmaceutically acceptable carrier is lactose, more preferably lactose monohydrate.
6. The dry powder composition for inhalation according to claim 5, wherein said lactose comprises coarse lactose and fine lactose.
7. The dry powder composition for inhalation according to any one of the preceding claims, wherein the D50 particle size of coarse lactose is between 25-300 pm, preferably 35-250 pm.
8. The dry powder composition for inhalation composition according to any one of the preceding claims, wherein the D50 particle size of fine lactose is between 0.01-25 pm, preferably 0.01-20 pm.
9. The dry powder composition for inhalation according to any one of the preceding claims, wherein the amount of the fine lactose is in the range of 0-30%, preferably 0.5-20%, more preferably 1-15% by weight of the total composition.
10. The dry powder composition for inhalation according to any one of the preceding claims, wherein the total amount of lactose is in the range of 50-99.9%, preferably 53-99.9%, more preferably 55-99.9% by weight of the total composition.
11. The dry powder composition for inhalation according to claim 1 , wherein the pharmaceutically acceptable surfactant is selected from the group comprising magnesium stearate, sodium stearate or mixtures thereof.
12. The dry powder composition for inhalation according to any one of the preceding claims, wherein the composition comprises;
- 0.1-50% by weight of micronized human insulin
- 0-30% by weight of fine lactose
- 50-99.9% by weight of total lactose
13. The dry powder composition for inhalation according to any one of the preceding claims, wherein the dosage form is capsule or blister.
14. A process for the preparation of the dry powder composition for inhalation comprises the following steps: plastering the inner wall of a container with %50 by weight of coarse lactose, adding fine lactose and micronized human insulin into the plastered container and mixing, adding %50 by weight of coarse lactose and mixing, adding surfactant and obtaining the final powder, filling the final powder mixture into blisters or capsules.
15. An inhaler for placing a blister pack comprising the blisters according to claim 14, wherein the inhaler comprises means to open blisters and to enable respective delivery of each unit dose.
16. An inhaler for placing the capsules according to claim 14, wherein the inhaler comprises means to open capsules and to enable respective delivery of each unit dose.
17. The inhalation composition for inhalation according any one of the claims 1 to 16, for use in the treatment of types I and II diabetes in mammalians.
PCT/TR2022/050445 2022-05-18 2022-05-18 Inhalation compositions comprising micronized human insulin WO2023224577A1 (en)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2001064188A1 (en) * 2000-02-29 2001-09-07 Quadrant Healthcare (Uk) Limited Therapeutic compositions for pulmonary delivery
US20060120969A1 (en) * 2004-12-03 2006-06-08 Microdrug Ag Medical product for inhalation containing glucagon-like peptide-1 (GLP-1)
US20120082727A1 (en) * 2010-09-30 2012-04-05 Chiesi Farmaceutici S.P.A. Use of magnesium stearate in dry powder formulations for inhalation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001064188A1 (en) * 2000-02-29 2001-09-07 Quadrant Healthcare (Uk) Limited Therapeutic compositions for pulmonary delivery
US20060120969A1 (en) * 2004-12-03 2006-06-08 Microdrug Ag Medical product for inhalation containing glucagon-like peptide-1 (GLP-1)
US20120082727A1 (en) * 2010-09-30 2012-04-05 Chiesi Farmaceutici S.P.A. Use of magnesium stearate in dry powder formulations for inhalation

Non-Patent Citations (2)

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Title
GUCHARDI, R. ET AL.: "Influence of fine lactose and magnesium stearate on low dose dry powder inhaler formulations", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 348, no. 1-2, 2008, pages 10 - 17, XP022393884, DOI: 10.1016/j.ijpharm.2007.06.041 *
KOU, X. ET AL.: "Physico-chemical aspects of lactose for inhalation", ADVANCED DRUG DELIVERY REVIEWS, vol. 64, no. 3, 2012, pages 220 - 232, XP028908201, DOI: 10.1016/j.addr.2011.11.004 *

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