A DRY POWDERED PHARMACEUTICAL COMPOSITION FOR INHALATION COMPRISING A THYROID HORMONE

Abstract

Dry powder compositions, suitable for inhalation via a suitable inhalation device, comprising a thyroid hormone drug and a non-reducing sugar or sugar alcohol as the sole carrier. The preparations hereof exhibit greater stability than those containing lactose monohydrate, a carrier commonly used for dry powder preparations.

Description

A DRY POWDERED PHARMACEUTICAL COMPOSITION FOR INHALATION COMPRISING A THYROID HORMONE TECHNICAL FIELD The invention relates to stable thyroid hormone drug compositions with a non-reducing sugar or sugar alcohol as the sole carrier, selected from trehalose, raffinose, mannitol, and isomaltitol, free of any other excipients, in the form of a dry powder suitable for inhalation via a suitable inhalation device. The preparations of the invention exhibit greater stability than those containing the carrier normally used for dry powder preparations, lactose monohydrate. PREVIOUS ART A search of the Prior Art revealed some documents that might be considered relevant to the present case. However, upon closer inspection of these documents, it was found that, as discussed below, they were not relevant. Document JP H05 306235 A discloses freeze-dried compositions comprising a parathyroid hormone as the active ingredient, along with an effective amount of sugars and sodium chloride. The sugar may be mannitol or trehalose. However, a parathyroid hormone is both structurally and functionally different from thyroid hormones such as levothyroxine and liothyronine. Parathyroid hormone is an 84-amino acid polypeptide that regulates extracellular calcium homeostasis. Furthermore, this patent application clearly states that only the combined use of a FRTBS.C.-30710441223 Digitallyssignediby RORTAFJIRAMITESodlNPIcan provide stability Date: 2019.04.10 11:49:27 -03:00 Reason: Digitally Signed by INPI - 1 Location: Buenos Aires, Argentina. The lyophilized composition is appropriate. Furthermore, this document indicates that decreased stability is observed with only one sugar. However, this document does not refer in any way to inhalation. The lyophilized compositions as disclosed herein are intended for reconstitution in an aqueous medium to form an injectable preparation. Such lyophilized compositions are neither intended nor suitable for inhalation. US Patent 2004 / 0033259 A1, cited in US Patent 8,333,192 B2, relates to a storage-stable dosage form of a thyroxine active drug composition. Levothyroxine sodium is the preferred active drug substance, mannitol is the preferred alditol present in the composition, and sucrose is the preferred saccharide. The preferred preparation is a compressed tablet. Alternatively, the preparation may be used to fill capsules (see paragraph

[0033] of this patent). However, no reference is made to any preparation that is useful or can be used as an inhalation powder. The only reference to powders in this patent pertains to the production of dosage forms such as tablets or capsules filled with solids. US patent 2016 / 0143855 A1 relates to pharmaceutical compositions comprising a thyroid hormone drug. The pharmaceutical composition may further comprise at least one carbohydrate, in particular a saccharide, and one or more pharmaceutically acceptable excipients (see claim 1). Although this document refers to powders as a solid dosage form, it does not refer to inhalation preparations. A person skilled in the art, however, is aware that there is no powder - 2 Suitable for inhalation of the respiratory system. The performance of a powder suggested for inhalation depends greatly on the physical properties of the carrier particles, such as particle size, morphology, and shape. US patent 8,333,192 B2 refers to a device comprising an inhaler suitable for administering a stable dry powder mixture, containing a mixture comprising a thyroid hormone drug, in particular levothyroxine sodium, and other additives such as lactose particles, sodium starch glycolate, magnesium stearate, and silicified talc. Example 14 of this US patent relates to a dry powder composition comprising mannitol, sucrose, microcrystalline cellulose, and magnesium stearate. From the outset, this is clearly not a composition suitable for inhalation. The components, such as microcrystalline cellulose, FD&C Yellow Aluminum Lake, and magnesium stearate, are certainly not suitable or intended for inhalation. Furthermore, Example 14 provides no information regarding the particle size of the active ingredients. Moreover, there is no mention of a solid carrier. Thus, the composition of Example 14 cannot be considered a dry powder pharmaceutical composition suitable for inhalation. In summary, the teaching of these documents may not be relevant to preparations relating to a dry powder thyroid hormone drug and a non-reducing sugar or sugar alcohol as the sole carrier for inhalation purposes. It is well known that approximately 60-80% of levothyroxine is absorbed after oral administration, primarily in the jejunum and ileum. Absorption occurs - 3 maximum on an empty stomach; therefore, it is common practice to advise patients to take levothyroxine on an empty stomach at least half an hour to one hour before meals or other medications. Administration via inhalation would minimize the potential for unwanted interactions between levothyroxine and other drugs or food, thereby increasing its bioavailability. In vitro permeability studies on Calu-3 cells indicated that levothyroxine can be effectively absorbed from the respiratory mucosa. Furthermore, levothyroxine shows high potential and is therapeutically effective in the microgram range and is therefore suitable for pulmonary absorption compared to orally administered drugs.The advantages of the pulmonary route also include a very large absorption surface (~80-140 m2), decreasing metabolism and effluent transport activity compared to the oral route, avoiding the first-pass effect and the possibility of a rapid onset of action. Lactose is commonly used in dry powder form for inhalation because it is highly crystalline and has satisfactory flow properties. However, lactose is a reducing sugar, making it incompatible with drugs containing primary amine fractions, such as thyroid hormones, namely levothyroxine and liothyronine. Therefore, it is necessary to develop a dry powder composition that exhibits high uniformity and stability, making it suitable for inhalation and overcoming the aforementioned obstacle. Surprisingly, dry powder compositions comprising a thyroid hormone drug and a single carrier among the non-reducing sugars / sugar alcohols—trehalose, raffinose, mannitol, isomaltitol—were found to be effective in the absence of... - 4 any other excipient, antioxidant or preservative, showed superior stability to that of the corresponding compositions based on lactose monohydrate. DETAILED DESCRIPTION OF THE INVENTION According to the invention, a thyroid hormone drug is diluted in a solid carrier to form a dry powder mixture that fluidizes when inhaled by the subject (patient). The thyroid hormone drug is either levothyroxine or liothyronine or their salts or a mixture thereof. The solid carrier is selected from the non-reducing sugars / sugar alcohols, trehalose, raffinose, mannitol, and / or isomaltitol. According to the invention, the thyroid hormone drug is in the form of a micronized powder with an average particle size between 1 and 10 micrometers or 2 and 5 micrometers. Reducing the particle size of the active ingredient to the extent mentioned above improves the overall performance of the dry powder composition, making it suitable for inhalation. Larger particles typically settle in the oral or pharyngeal cavity, from which they can be easily removed, while smaller particles may not settle at all or settle very slowly. Accordingly, the particle size of the carrier is selected to be in the range of 20 to 400 micrometers or 40 to 200 micrometers, with the aim of improving flow and reducing degradation during delivery of the active ingredient to the lungs. The measurement of particle size (i.e., average particle size) as required in the present invention is well known to a person skilled in the art. 5 Typically, particle size analysis was performed using a laser diffraction particle size analyzer (i.e., a Fritsch GmbH “Analysette 22 Laser Particle Calibrator”). The volume mean diameter and other particle size parameters (D10%, D50%, and D90%) were automatically calculated using the supplied software. Approximately 200–300 mg of sample were dispersed in purified water and placed in the measuring cell. Particle size measurement was performed under agitation conditions during the experiment. The results are the mean and standard deviation of five determinations. Thus, the present invention relates to a dry powdered pharmaceutical composition consisting of a micronized powder of a thyroid hormone with an average particle size between 1 and 10 micrometers, diluted in solid carrier particles of a size in the range of 20 to 400 micrometers, suitable for inhalation, wherein the thyroid hormone drug is either levothyroxine or liothyronine or their salts, comprising as the sole carrier a non-reducing sugar or sugar alcohol and the absence of any other excipient, antioxidant or preservative. According to a particular aspect of the present invention, a dry powdered pharmaceutical composition comprises a micronized powder of a thyroid hormone with an average particle size between 1 and 10 micrometers and solid carrier particles with a size in the range of 20 to 400 micrometers, wherein the carrier particles are made of non-reducing sugars or sugar alcohols. Preferably, the dry powdered pharmaceutical composition essentially—or - 6 optionally only - consists of the micronized thyroid hormone powder and solid carrier particles. In a preferred embodiment, the thyroid hormone drug is levothyroxine, liothyronine, or a pharmaceutically acceptable salt thereof. The non-reducing sugar may be selected from sucrose, trehalose, raffinose, stachyose, and verbascose. The non-reducing sugar alcohol may be selected from mannitol and isomaltitol. According to the invention, the preparation comprises 5–500 or 10–400 micrograms of the thyroid hormone drug and 99.995–99.950 or 99.990–99.600 mg of the solid carrier. Accordingly, the amount of the thyroid hormone drug represents 0.005–0.5% or 0.01–0.4% of the dry powder composition, while the amount of the solid carrier represents 99.500–99.995% or 99.600–99.990% of the dry powder composition. According to the invention, the dry powder compositions are prepared following a geometric dilution process. First, the micronized thyroid hormone drug is placed in an isolator, where the required amount is weighed and mixed with an equal amount of the solid carrier. The mixture of the two powders is then finely ground and crushed until completely blended. Subsequently, an amount of the remaining carrier equal to that of the ground powder is added, and the grinding process is repeated. This process is repeated until the total amount of carrier is incorporated into the mixture. The final dry mixture is stored in hermetically sealed amber glass bottles and tested for homogeneity and levothyroxine content. - 7 The invention is further described in the following representative, non-limiting examples. Example 1 The following example describes a process for preparing a dry powder composition comprising levothyroxine sodium and trehalose. The preparation of the dry powder composition took place in a rotating drum placed in an insulator. 0.100 mg of levothyroxine sodium hydrate and 0.100 mg of trehalose were placed in the drum and mixed for 10 min at 15 rpm. Then, 0.200 mg of carrier was added to the drum and the mixture was stirred for 10 min at 15 rpm. Next, 0.400 mg of trehalose was added to the drum and the mixture was stirred for 10 min at 15 rpm. Finally, 0.800 mg of trehalose was added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 1,600 mg of trehalose were added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 3,200 mg of trehalose were added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 13,333 mg of trehalose were added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 33.333 mg of trehalose were added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 46.934 mg of trehalose were added to the drum and the mixture was stirred for another 10 min at 15 rpm. The final dry mixture was stored in airtight amber glass bottles and analyzed for homogeneity (uniformity of the mixture) and levothyroxine content. Mixture uniformity was determined by measuring the levothyroxine assay using high-performance liquid chromatography (HPLC). - 8 High-Performance Liquid Chromatography”), on samples collected from 10 different locations on the drum. After long-term storage (18 months), a stability study was performed under normal conditions (25 ± 2 °C / 60 ± 5% RH), following a test protocol with a time interval of 6 months. Example 2 The following example describes a process for preparing a dry powder composition comprising levothyroxine sodium and raffinose. The preparation of the dry powder composition is carried out in a rotating drum placed in an insulator. 0.100 mg of levothyroxine sodium hydrate and 0.100 mg of raffinose were placed in the drum and mixed for 10 min at 15 rpm. Then, 0.200 mg of carrier was added to the drum and the mixture was stirred for 10 min at 15 rpm. Next, 0.400 mg of raffinose was added to the drum and the mixture was stirred for 10 min at 15 rpm. Finally, 0.800 mg of raffinose was added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 1,600 mg of raffinose were added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 3,200 mg of raffinose were added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 13,333 mg of raffinose were added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 33.333 mg of raffinose were added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 46.934 mg of raffinose were added to the drum and the mixture was stirred for 10 min at 15 rpm. The final dried mixture is stored in tightly sealed amber glass bottles and analyzed according to its - 9. Homogeneity (uniformity of the mixture) and levothyroxine analysis. Mixture uniformity was determined by measuring levothyroxine analysis using high-performance liquid chromatography (HPLC) on samples collected from 10 different locations within the drum. After long-term storage (18 months), a stability study was conducted under normal conditions (25 ± 2 °C / 60 ± 5% RH), following a 6-month interval testing protocol. Example 3 The following example describes a process for preparing a dry powder composition comprising levothyroxine sodium and mannitol. The preparation of the dry powder composition is carried out in a rotating drum placed in an insulator. 0.100 mg of levothyroxine sodium hydrate and 0.100 mg of mannitol were placed in the drum and mixed for 10 min at 15 rpm. Then, 0.200 mg of carrier was added to the drum and the mixture was stirred for 10 min at 15 rpm. Next, 0.400 mg of mannitol was added to the drum and the mixture was stirred for 10 min at 15 rpm. Finally, 0.800 mg of mannitol was added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 1,600 mg of mannitol were added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 3,200 mg of mannitol were added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 13,333 mg of mannitol were added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 33.333 mg of mannitol were placed in the drum and the mixture was stirred for 10 min at 15 rpm. Then, 46.934 mg of mannitol were added. The mixture was placed in the drum and stirred for 10 minutes at 15 rpm. The final dry mixture was stored in airtight amber glass bottles and analyzed for homogeneity (mixture uniformity) and levothyroxine content. Mixture uniformity was determined by measuring levothyroxine content using high-performance liquid chromatography (HPLC) on samples collected from 10 different locations within the drum. After long-term storage (18 months), a stability study was conducted under normal conditions (25 ± 2 °C / 60 ± 5% RH), following a 6-month interval testing protocol. Example 4 The following example describes a process for preparing a dry powder composition comprising levothyroxine sodium and isomaltitol. The preparation of the dry powder composition is carried out in a rotating drum placed in an insulator. 0.100 mg of levothyroxine sodium hydrate and 0.100 mg of isomaltitol were placed in the drum and mixed for 10 min at 15 rpm. Then, 0.200 mg of carrier was added to the drum and the mixture was stirred for 10 min at 15 rpm. Next, 0.400 mg of isomaltitol was added to the drum and the mixture was stirred for 10 min at 15 rpm. Finally, 0.800 mg of isomaltitol was added to the drum and the mixture was stirred for 10 min at 15 rpm. Next, 1,600 mg of isomaltitol was added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 3,200 mg of isomaltitol was added to the drum and the mixture was stirred for 10 min at 15 rpm. Finally, 13,333 mg of isomaltitol was added to the drum and the mixture was stirred for 10 min at 15 rpm.Then, 33.333 mg of isomaltitol were added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, it was. - 11. 46.934 mg of isomaltitol were added to the drum, and the mixture was stirred for 10 min at 15 rpm. The final dry mixture was stored in airtight amber glass bottles and analyzed for homogeneity (mixture uniformity) and levothyroxine content. Mixture uniformity was determined by measuring levothyroxine content using high-performance liquid chromatography (HPLC) on samples collected from 10 different locations within the drum. After long-term storage (18 months), a stability study was conducted under normal conditions (25 ± 2 °C / 60 ± 5% RH) following a 6-month interval testing protocol. A comparative example (Example 5) was performed to prepare a dry powder composition of levothyroxine sodium with the commonly used lactose monohydrate inhalation carrier, following the method of the invention. In this context, the preparation of the dry powder composition is carried out in a rotating drum placed in an insulator. 0.100 mg of levothyroxine sodium hydrate and 0.100 mg of lactose monohydrate are placed in the drum and mixed for 10 min at 15 rpm. Then, 0.200 mg of carrier is added to the drum and the mixture is stirred for 10 min at 15 rpm. Next, 0.400 mg of lactose monohydrate is added to the drum and the mixture is stirred for 10 min at 15 rpm. Finally, 0.800 mg of lactose monohydrate is added to the drum and the mixture is stirred for 10 min at 15 rpm. Then, 1,600 mg of lactose monohydrate were added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 3.200 mg of lactose monohydrate were added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, 13.333 mg of lactose monohydrate were added to the drum and the mixture was stirred for 10 min at 15 rpm. Then, they were added. 33.333 mg of lactose monohydrate was added to the drum, and the mixture was stirred for 10 minutes at 15 rpm. Then, 46.934 mg of lactose monohydrate was added to the drum, and the mixture was stirred for another 10 minutes at 15 rpm. The final dry mixture was stored in airtight amber glass bottles and analyzed for homogeneity (mixture uniformity) and levothyroxine content. Mixture uniformity was determined by measuring levothyroxine content using high-performance liquid chromatography (HPLC) on samples collected from 10 different locations within the drum. After long-term storage (18 months), a stability study was conducted under normal conditions (25 ± 2 °C / 60 ± 5% RH) following a 6-month interval testing protocol. Table 1. Dry powder compositions described in Examples 1-5. Ingredient (Average Particle Size) Example 1 Example 2 Example 3 Example 4 Example 5 Levothyroxine sodium hydrate (2.39 μm) 0.100 mg 0.100 mg 0.100 mg 0.100 mg 0.100 mg Trehalose (64 μm) 99,900 mg Raffinose (88 μm) 99,900 mg Mannitol (100 μm) 99,900 mg Isomaltitol (41 μm) 99,900 mg Lactose monohydrate (48 μm) 99,900 mg It is within the skills of a trained person to proceed with the preparation of powder mixtures - 13 different strengths of thyroid hormone drug dried by the following procedure described in Examples 1-4 and mixing appropriate amounts of a selected carrier. The homogeneity of the mixture was determined by measuring the levothyroxine content using high-performance liquid chromatography (HPLC) in samples collected from 10 different locations within the drum. All compositions showed high homogeneity, suggesting that they are suitable for inhalation. Table 2. Mixing uniformity of dry powder compositions of levothyroxine (100μg / 100 mg) Levothyroxine Analysis (%) Sample Example 1 Example 2 Example 3 Example 4 Example 5 1 102.2 104.8 99.1 99.2 102.5 2 101.5 104.1 100.2 99.2 103.3 3 99.9 103.9 98.8 97.9 103.5 4 101.9 104.9 99.5 97.8 102.1 5 102.2 104.7 98.2 97.1 103.0 6 102.8 105.2 99.2 97.2 103.0 7 101.8 105.4 98.9 101.1 103.7 8 102.3 105.9 98.7 101.5 103.1 9 102.5 104.8 99.5 101.5 103.0 10 101.7 105.3 99.2 100.9 102.6 Average 101.9 104.9 99.1 99.3 103.0 SD 0.80 0.60 0.54 1.78 0.48 RSD 0.78 0.57 0.55 1.79 0.47 Where SD: Standard deviation, RSD: Relative standard deviation Dry powder compositions of levothyroxine sodium from Examples 1-4 were stored in tightly sealed amber glass bottles for 18 months under normal conditions, namely at 25 ± 2 °C and 60 ± 5% Relative Humidity and - 14 The stability of the dry powder studied in terms of levothyroxine (%) analysis and impurity profile. The stability results were compared with those obtained from a corresponding dry powder composition of levothyroxine sodium with lactose monohydrate (Comparative Example 5) stored under the same temperature and relative humidity conditions. Dry powder composition of levothyroxine sodium with trehalose showed a 3.2% loss of potency of levothyroxine sodium after 18 months of storage at 25 ± 2 °C / 60 ± 5% Relative Humidity, which was significantly higher compared to the 13.6% loss of potency of levothyroxine analysis of levothyroxine dry powder with lactose monohydrate. Table 3. Stability study of dry powder compositions of levothyroxine sodium Levothyroxine Sodium Dry Composition Powder Levothyroxine Analysis (%) Storage Conditions: 25 ± 2 °C / 60 ± 5% RH Example Carrier t = 0 6 months 12 months 18 months Example 1 Trehalose 101.9 100.6 99.9 98.7 Example 2 Raffinose 104.9 103.8 102.7 101.1 Example 3 Mannitol 99.1 97.3 96.3 94.9 Example 4 Imaltitol 99.3 98.4 96.4 94.7 Example 5 Lactose Monohydrate 103.0 96.6 93.9 89.4 The impurity profile of dry powder compositions of levothyroxine of the invention after 18 months of storage at 25 ± 2 °C / 60 ± 5% RH verifies the superiority of the dry composition of levothyroxine sodium in - 15 powder with the carriers trehalose, raffinose, mannitol, and isomaltitol compared to lactose monohydrate. The composition with lactose monohydrate shows a high percentage of unspecified impurities (4.4%), probably due to the formation of adducts between levothyroxine and lactose. Table 4. Impurity profile of dry powder compositions of levothyroxine after 18 months of storage at 25 ± 2 °C / 60 ± 5% RH. Impurity Example 1 Example 2 Example 3 Example 4 Example 5 Liothyronine (%) 0.17 0.16 0.21 0.24 0.82 TETRAC (%) 0.08 0.10 0.11 0.15 0.19 Benzoic acid- T4 (%) 0.09 0.11 0.13 0.19 0.25 Total other unspecified impurities (%) 0.58 0.64 0.78 0.91 4.4 Total impurities (%) 0.92 1.01 1.23 1.49 5.66 -

Claims

1. A dry powdered pharmaceutical composition characterized in that it consists of a micronized powder of a thyroid hormone with an average particle size between 1 and 10 micrometers, diluted in solid carrier particles of a size in the range of 20 to 400 micrometers, suitable for inhalation, wherein the thyroid hormone drug is levothyroxine or a salt thereof, comprising as the sole carrier a non-reducing sugar or non-reducing sugar alcohol, the non-reducing sugar being selected from sucrose, trehalose, raffinose, stachyose, or verbascose, and the non-reducing sugar alcohol being selected from mannitol and isomaltitol, and the absence of any other excipient, antioxidant, or preservative. Two claims follow.