JP2009513529A - Pharmaceutical formulations containing magnesium stearate - Google Patents

Abstract

  The present invention relates to the use of magnesium stearate to inhibit or reduce the chemical interaction between an active ingredient substance and the carrier in a solid pharmaceutical formulation in which the active ingredient substance is likely to interact with the carrier. An inhalable solid pharmaceutical formulation comprising an active ingredient substance susceptible to chemical interaction with lactose, a carrier, and magnesium stearate is also provided along with its use and methods therefor.

Description

  The present invention relates to a solid pharmaceutical formulation comprising a pharmaceutical substance as an active ingredient, a carrier, and magnesium stearate. The present invention also relates to the use of magnesium stearate to inhibit or reduce chemical reaction or degradation of the active ingredient material in the presence of a carrier. The present invention also relates to the use of magnesium stearate to stabilize a pharmaceutical substance that is an active ingredient in the presence of a carrier.

  An important requirement for pharmaceutical formulations is that they must be stable when stored under a range of different conditions. Active ingredient substances are known to be unstable to heat, light or moisture, and when preparing and storing such substances, the pharmaceutical product should have a reasonable shelf life. It is known that various precautions must be taken to ensure that they remain in an acceptable state for use over a reasonable period of time. Instability of the drug substance may also result from contact with one or more other ingredients present in the formulation, eg, ingredients present as excipients.

  It is common practice in the pharmaceutical arts to formulate an active ingredient substance with substances known as excipients that may be required as carriers, diluents, fillers, bulking agents, binders and the like. Such excipients are often used to increase the amount of the pharmaceutical formulation when the active ingredient substance is present in very small amounts. Such materials are generally chemically inert. However, over long storage periods, or under excessive heat or humidity conditions, in the presence of other materials, such inert materials can undergo or participate in chemical degradation reactions.

  Examples of carrier substances widely used in solid pharmaceutical preparations include reducing sugars such as lactose (lactose), maltose (malt sugar), and glucose (glucose). Lactose is particularly widely used. Lactose is generally considered an inert excipient.

  However, certain active ingredient substances have been found to undergo chemical reactions in the presence of lactose and other reducing sugars. For example, fluoxetine hydrochloride (sold under the trade name Prozac®) is capable of degrading when present together with lactose excipients in solid tablets with Wirth et al. (J. Pharm. Sci. , 1998, 87, 31-39). It is hypothesized that this decomposition is caused by the formation of adducts by Maillard reaction, and a number of initial Maillard reaction intermediates have been revealed. The authors conclude that medicinal substances that are secondary or primary amines undergo a Maillard reaction with lactose under pharmaceutically relevant conditions.

  The inventors have found that under accelerated stability assessment conditions, certain inhalable active ingredient substances are also degraded in the presence of lactose, possibly again by Maillard reaction.

  For example, certain inhalable dry powder pharmaceuticals are susceptible to moisture, as reported in WO 00/28979 (SkyePharma AG). It has been found that the presence of moisture hinders the physical interaction between the carrier and the drug substance and thus the efficiency of drug delivery. Such interference with the physical interaction between the carrier and the pharmaceutical substance is distinguished from chemical instability resulting from degradation.

  A widely used excipient in solid pharmaceutical formulations is magnesium stearate, which is often included as a lubricant. WO00 / 28979 (SkyePharma AG) has a dry powder formulation for inhalation to improve moisture resistance and to reduce the effect of osmotic moisture on fine particle fraction (FPF) of the inhaled formulation. The use of magnesium stearate is described therein. WO00 / 53158 (Chiesi) describes a powder used in a dry powder inhaler containing an active ingredient and a carrier, the carrier containing a lubricant, for example, magnesium stearate, among others. An optional powder is described.

  WO / 96/23485 (Coordinated Drug Development Ltd), WO01 / 78694 and WO01 / 78695 (Vectura Limited) describe powders for use in dry powder inhalers, including active ingredient particles and carrier particles. In this case, the carrier contains an additive capable of promoting the release of the active particles from the carrier particles. Possible additive substances include amino acids, phospholipids, fatty acids and fatty acid derivatives such as salts and esters, especially magnesium stearate.

  The inventors have surprisingly found that the chemical interaction between the active ingredient substance and the carrier can be suppressed or reduced by the presence of magnesium stearate.

  Accordingly, in a first aspect, the present invention provides a solid pharmaceutical formulation in which an active ingredient substance is likely to chemically interact with a carrier, and suppresses or reduces the chemical interaction between the active ingredient substance and the carrier. Provide the use of magnesium stearate.

  The present invention also includes the use of magnesium stearate for inhibiting or reducing chemical degradation of an active ingredient substance in a solid pharmaceutical formulation comprising the active ingredient substance and a carrier, wherein the active ingredient substance is likely to chemically interact with the carrier I will provide a. This improves the chemical stability of the active substance in the formulation during long-term storage.

  In a second aspect, the present invention provides a solid pharmaceutical formulation comprising (a) an active ingredient substance that is susceptible to chemical interaction with a carrier, (b) a carrier, and (c) magnesium stearate.

  In a third aspect, the present invention provides a method for reducing or suppressing a chemical interaction between an active ingredient substance susceptible to chemical interaction and a carrier, the active ingredient substance and the carrier comprising magnesium stearate Is provided. The present invention also provides a method for inhibiting chemical degradation of an active ingredient substance in a formulation comprising a carrier and an active ingredient substance, the method comprising mixing the active ingredient substance and the carrier with magnesium stearate. To do.

  A pharmaceutical formulation prepared according to the invention has a higher chemical stability than a corresponding formulation without a third substance.

  In the present invention, magnesium stearate is referred to as a third substance. “Third substance” refers to the active ingredient, the pharmaceutical substance (s) (“first substance”) and the bulk carrier material (s) (“second substance”) Is used herein to mean a compound used in the formulation. In some cases, more than one third substance may be used. In some cases, further substances, possibly called “fourth substances”, may be present, for example as lubricants. Any particular third or fourth substance may have more than one effect.

  The present invention finds particular use in formulations where the carrier is a reducing sugar such as lactose, maltose or glucose (eg monohydrate glucose or anhydroglucose). In a preferred embodiment, the carrier is lactose. Another carrier includes maltodextrin.

  The optimum amount of magnesium stearate present in a particular composition will vary depending on the identity of the active pharmaceutical ingredient present, the size of the particles, and various other factors. In general, magnesium stearate is preferably present in an amount of 0.1 to 20% w / w (% w / w) based on the total weight of the composition. More preferably, the magnesium stearate is present in an amount of 0.2 to 10% w / w based on the total weight of the composition. Even more preferably, the magnesium stearate is preferably present in an amount of 0.3-6% w / w, for example 0.5-4% w / w.

  The active ingredient material is typically present in an amount of 0.01 to 50% w / w based on the total weight of the composition. Preferably, the active ingredient substance is in an amount of 0.02 to 10% w / w, more preferably in an amount of 0.03 to 5% w / w, such as 0.05 to 1% w / w, for example 0.1% w / w. Present in an amount of%.

Preferably, the medicinal substance which is the active ingredient is one containing a primary or secondary amine group. Thus, for example, the pharmaceutical substance can comprise the group Ar—CH (OH) —CH ₂ —NH—R.

The group Ar is for example selected from the group of formulas (a), (b), (c) and (d):

In the above formula,
R ¹² is hydrogen, halogen,-(CH ₂ ) _q OR ¹⁶ , -NR ¹⁶ C (O) R ¹⁷ , -NR ¹⁶ SO ₂ R ¹⁷ , -SO ₂ NR ¹⁶ R ¹⁷ , -NR ¹⁶ R ¹⁷ ,- Represents OC (O) R ¹⁸ or OC (O) NR ¹⁶ R ¹⁷ and R ¹³ represents hydrogen, halogen or C _1-4 alkyl, or
R ¹² represents —NHR ¹⁹ and R ¹³ and —NHR ¹⁹ together form a 5- or 6-membered heterocyclic ring;
R ¹⁴ represents hydrogen, halogen, —OR ¹⁶ or —NR ¹⁶ R ¹⁷ ;
R ¹⁵ represents hydrogen, halogen, haloC _1-4 alkyl, —OR ¹⁶ , —NR ¹⁶ R ¹⁷ , —OC (O) R ¹⁸ , or OC (O) NR ¹⁶ R ¹⁷ ;
R ¹⁶ and R ¹⁷ each independently represent hydrogen or C _1-4 alkyl, or R in the groups —NR ¹⁶ R ¹⁷ , —SO ₂ NR ¹⁶ R ¹⁷ , and —OC (O) NR ¹⁶ R ^{17 16} and R ¹⁷ independently represent hydrogen or C _1-4 alkyl, or together with the nitrogen to which they are attached form a 5-, 6-, or 7-membered nitrogen-containing ring;
R ¹⁸ may be unsubstituted or substituted with one or more substituents selected from halogen, C _1-4 alkyl, hydroxy, C _1-4 alkoxy, or halo C _1-4 alkyl. Represents an optionally substituted aryl (eg phenyl or naphthyl) group;
q is zero or an integer of 1 to 4.

In certain embodiments, the group Ar is as defined above except that R ¹² is not hydrogen.

Within the definitions of (a) and (b) above, preferred groups can be selected from the following groups (i) to (xxi):

The dotted lines at (xvi) and (xix) in the above formula represent double bonds that may be present.

  In a preferred embodiment Ar represents a group (i) as defined above.

  In another embodiment Ar represents a group (iii) as defined above.

The group R preferably represents a partial structure represented by the following formula:
-ABCD
In the above formula,
A can represent (CH ₂ ) _m , where m is an integer from 1 to 10;
B may represent a heteroatom (eg oxygen) or a bond;
C may represent (CH ₂ ) _n , where n is an integer from 1 to 10;
D can represent an aryl group (eg, an optionally substituted phenyl or pyridyl group).

  Pharmaceutical substances that can be formulated according to the invention include international patent applications WO 02/066422, WO 02/070490, WO 02/076933, WO 03/024439, WO 03/072539, WO 03/091204, WO 04 / 016578, WO2004 / 022547, WO 2004/037807, WO 2004/037773, WO 2004/037768, WO 2004/039762, and WO 2004/039766.

Specific pharmaceutical substances that can be formulated according to the present invention include the following:
3- (4-{[6-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) hexyl] oxy} butyl) benzenesulfonamide (e.g. its As cinnamate);
3- (3-{[7-({(2R) -2-hydroxy-2- [4-hydroxy-3-hydroxymethyl) phenyl] ethyl} -amino) heptyl] oxy} propyl) benzenesulfonamide;
4-{(1R) -2-[(6- {2-[(2,6-dichlorobenzyl) oxy] ethoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol;
4-{(1R) -2-[(6- {4- [3- (cyclopentylsulfonyl) phenyl] butoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol;
As well as their salts, solvates, and other physiologically functional derivatives.

  Other pharmaceutical substances that can be formulated according to the present invention include salmeterol, (R) -salmeterol, salbutamol, (R) -salbutamol, formoterol, (R, R) -formoterol, fenoterol, etanterol, naminterol, clenbuterol , Pyrbuterol, flerobuterol, reproterol, bambuterol, terbutaline, and their salts, solvates, and other physiologically functional derivatives.

  The active pharmaceutical ingredient may be in the free acid or base form, or may be present as a salt, solvate, or other physiologically functional derivative. Salts and solvates suitable for use in medicine are those in which the counterion or associated solvent is pharmaceutically acceptable.

  Suitable salts for use in the present invention include those formed with organic acids or bases and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, triphenylacetic acid, phenylacetic acid, substituted phenylacetic acid For example, methoxyphenylacetic acid, sulfamic acid, sulfanilic acid, succinic acid, oxalic acid, fumaric acid, maleic acid, malic acid, glutamic acid, aspartic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, arylsulfonic acid (for example, p-toluene) Sulfonic acid, benzene sulfonic acid, naphthalene sulfonic acid or naphthalene disulfonic acid), salicylic acid, glutaric acid, gluconic acid, tricarballylic acid, mandelic acid, cinnamic acid, substituted cinnamic acids (eg methyl, methoxy, halo, or phenyl substituted cinnamics) Acids such as 4-methyl and 4-methoxycinnamic acid And α-phenylcinnamic acid (E or Z isomers or a mixture of the two)), ascorbic acid, oleic acid, naphthoic acid, hydroxynaphthoic acid (eg 1- or 3-hydroxy-2-naphthoic acid), naphthalene acrylic acid (Eg naphthalene-2-acrylic acid), benzoic acid, 4-methoxybenzoic acid, 2- or 4-hydroxybenzoic acid, 4-chlorobenzoic acid, 4-phenylbenzoic acid, benzeneacrylic acid (eg 1,4-benzene) Diacrylic acid), and those formed from isethionic acid. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and dicyclohexylamine and N-methyl-D- And salts with organic bases such as glucamine.

In the present invention, physiologically functional derivatives of pharmaceutical substances can also be used. The term “physiologically functional derivative” means a chemical derivative of a compound that has the same physiological function as the free compound, eg, by being convertible into the free compound in the body. In accordance with the present invention, examples of physiologically functional derivatives include esters, eg, compounds in which the hydroxyl group is converted to a C _1-6 alkyl, aryl, aryl C _1-6 alkyl, or amino acid ester. .

The pharmaceutical substance that is the active ingredient is most preferably a long acting selective β ₂ adrenergic receptor agonist. Such compounds are found in asthma, chronic obstructive pulmonary disease (COPD) (eg, chronic bronchitis and wheezing bronchitis, emphysema), respiratory infections, and upper respiratory tract diseases (eg, rhinitis (seasonal rhinitis and allergic) It has use in the prevention and treatment of various clinical conditions including diseases associated with reversible airway obstruction such as rhinitis)).

  Other conditions that can be treated include preterm birth, depression, congestive heart failure, skin diseases (eg inflammatory skin disease, allergic skin disease, psoriatic skin disease, and proliferative skin disease), digestive acidity Examples include pathological conditions in which a reduction in (peptic acidity) is desirable (for example, peptic ulcer and gastric ulcer), and muscle fatigue disease.

  The formulations to which the present invention can be applied include oral administration, parenteral (eg, subcutaneous, intradermal, intramuscular, intravenous, and intraarticular), inhalation (eg, various types of metered pressure aerosols, nebulizers, or Particulate dust or mist that can be generated by an insufflator, rectal administration, and topical (eg skin, buccal, sublingual, and intraocular) administration (however, the most suitable route of administration is eg recipient Suitable formulations), which may vary depending on the condition and disorder. The formulations can conveniently be presented in unit dosage form and can be prepared by any method well known in the pharmaceutical art. All methods include the step of bringing into association the active ingredient with the carrier and the third material magnesium stearate and other auxiliary ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient, lactose, magnesium stearate and other auxiliary ingredients, and then, if necessary, shaping the preparation into the desired formulation.

  Formulations of the present invention suitable for oral administration can be provided as individual units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient as a powder or granules. The medicinal substance which is the active ingredient can also be provided as a bolus, electuary or paste.

  A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets are prepared by mixing the active ingredient in free-flowing form such as powders or granules, optionally with a binder, lubricant, inert diluent, lubricating surfactant or dispersant, in a suitable machine. It can be prepared by compression molding. Molded tablets can be made by molding, in a suitable machine, the powdered compound mixture moistened with an inert liquid diluent. Tablets can optionally be coated or scored and can be formulated to give delayed or controlled release of the active ingredient therein.

  Preparations for parenteral administration include sterile powders, granules and tablets intended to be dissolved immediately prior to administration. The formulation can be provided in unit-dose containers or multi-dose containers, such as sealed ampoules or vials, in a lyophilized state requiring only the addition of a sterile liquid carrier such as saline or water for injection just prior to use. Can be stored.

  For preparations for topical administration in the mouth, such as buccal administration or sublingual administration, lozenges (oral tablets) containing the active ingredient in a flavor base such as sucrose, acacia or tragacanth, and active ingredients containing gelatin, glycerin or sucrose And lozenges (pastille) contained in bases such as Acacia.

  The present invention finds particular application in dry powder compositions, particularly dry powder compositions for topical delivery by inhalation to the lungs.

  Dry powder compositions delivered topically to the lungs by inhalation were made, for example, in capsules and cartridges made of gelatin, for example used in inhalers and insufflators, or made of laminated aluminum foil, for example Can be provided in a blister. This formulation package would be suitable for unit dose delivery and multiple dose delivery. For multi-dose delivery, the formulation can be pre-quantified (eg as in Diskus (see GB 2242134) or in Diskhaler (see GB 2178965, 2129691, and 2169265)), Alternatively, it can be quantified during use (eg as in Turbuhaler [see EP 69715 or EP0237507]). An example of a unit dose device is Rotahaler (see GB 2064336). The Diskus inhaler includes a bottom sheet having a plurality of recesses arranged at intervals in the length direction, and a plurality of containers (sealed) sealed (separated) so as to be peeled off while being sealed to the bottom sheet. Each container includes an elongate strip formed from a lid sheet defining an inhalable formulation containing the active compound). Preferably, the strip is sufficiently flexible and rollable.

  Agents for administration by inhalation desirably have a controlled particle size. The optimum particle diameter for inhalation into the bronchial system is usually 1 to 10 μm, preferably 2 to 5 μm when expressed in terms of mass mean diameter (MMD). Particles larger than 20 μm in diameter are generally too large to reach the small airways when inhaled. In order to achieve these particle sizes, the generated active ingredient substance particles can be reduced in size by conventional methods such as micronization. The desired fraction can be separated and removed by air classification or air sieving. Preferably, the particles are made of crystals. In general, the particle size of the carrier (eg lactose) is much larger than the pharmaceutical substance within the present invention. It is also desirable that other substances than the active pharmaceutical substance have a larger particle size than the active pharmaceutical substance. When the carrier is lactose, it is typically present as ground lactose, for example having a mass average diameter (MMD) of 60-90 μm and a particle diameter of less than 15% of less than 15 μm.

  Magnesium stearate typically has a particle size of 1-50 μm, more preferably 1-20 μm, for example 1-10 μm.

  Preferred unit dosage formulations are those containing an effective dosage as described above or an appropriate proportion thereof of the active ingredient.

  In addition to the ingredients detailed above, it should be understood that the formulations of the present invention may include other materials commonly used in the art related to the type of formulation in question, eg suitable for oral administration The formulation may include a flavoring agent.

The compounds and pharmaceutical formulations according to the invention can be used in combination with one or more other therapeutic agents, i.e. can contain them, e.g. β-agonists are anti-inflammatory agents (e.g. corticosteroids) Or NSAID), anticholinergic drugs (especially M ₁ , M ₂ , M ₁ / M ₂ , or M ₃ receptor antagonists), other β ₂ -adrenergic receptor agonists, anti-infective drugs (eg antibiotics, antivirals) Drug), or in combination with one or more other therapeutic agents selected from antihistamines.

  Suitable corticosteroids include methylprednisolone, prednisolone, dexamethasone, fluticasone propionate, 6α, 9α-difluoro-17α-[(2-flunylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo -Androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4- Diene-17β-carbothioic acid S- (2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone ester (eg 17-propionate ester or 17,21-dipropionate ester), budesonide, flunisolide, mometasone Esters (eg furoate), triamcinolone acetonide, rofleponide, ciclesonide, butyxocortopropionate, RPR-106541 , And ST-126.

  Suitable NSAIDs include cromoglycate sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (eg, theophylline, PDE4 inhibitors or mixed PDE3 / PDE4 inhibitors), leukotriene antagonists, leukotriene synthesis inhibitors, iNOS inhibitors , Tryptase and elastase inhibitors, β-2 integrin antagonists and adenosine receptor agonists or antagonists (eg adenosine 2a agonists), cytokine antagonists (eg chemokine antagonists), or cytokine synthesis inhibitors.

Suitable anticholinergics are compounds that act as antagonists to muscarinic receptors, in particular compounds that are antagonists of the M ₁ and M ₂ receptors. Exemplary compounds include the belladonna plant alkaloids exemplified by analogs of atropine, scopolamine, homatropine, hyoscyamine. Since these compounds are tertiary amines, they are usually administered as salts.

  Preferred anticholinergic agents include ipratropium (eg, as bromide), oxitropium (eg, as bromide), and tiotropium (eg, as bromide) [CAS-139404-48-1] sold under the trade name Atrovent. .

Suitable antihistamines (also called H ₁ -receptor antagonists) include one or more of a number of known antagonists that inhibit H ₁ -receptors and are safe for human use. All of these are reversible, competitive inhibitors of the interaction between histamine and H ₁ -receptors. Examples of preferred antihistamines include metapyrylene and loratadine.

  The invention further includes asthma, chronic obstructive pulmonary disease (COPD) (eg, chronic and wheezing bronchitis, emphysema), respiratory infections, and upper respiratory tract diseases (eg, rhinitis (seasonal rhinitis and allergic rhinitis). There is provided the use of an inhalable solid pharmaceutical formulation according to the present invention for the manufacture of a medicament for the treatment of diseases associated with reversible airway obstruction such as The invention also includes administering an inhalable solid pharmaceutical formulation according to the invention to a patient in need thereof, asthma, chronic obstructive pulmonary disease (COPD), chronic or wheezing bronchitis, emphysema, respiratory organs Provide treatment for infections, upper respiratory tract disease, or rhinitis (including seasonal rhinitis and allergic rhinitis).

  In a further aspect, the present invention provides a solid pharmaceutical formulation comprising combining (a) an active ingredient substance that is susceptible to interaction with a carrier, (b) a carrier, and (c) magnesium stearate in one or more steps. A method of preparation is provided.

Test Compound In the following examples, the pharmaceutical compound “Compound X” is 3- (4-{[6-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] Ethyl} amino) hexyl] oxy} -butyl) benzene-sulfonamide cinnamate. The synthesis of compound X is described in Examples 45 and 46 of WO 02/066422.

Method
Blend Preparation Lactose monohydrate was obtained from Borculo Domo Ingredients in the form of BP / USNF. Prior to use, the lactose monohydrate was sieved through a coarse screen (mesh size 500 microns) to deagglomerate. Compound X was pulverized with an APTM pulverizer prior to use to obtain MMD (average mass diameter) of 2 to 5 microns.

  Magnesium stearate was obtained from Peter Greven and used as delivered (MMD <10 microns).

  Combine this magnesium stearate with lactose monohydrate and blend in a high shear mixer (QMM, PMA, or TRV series mixer) or low shear tumbling blender (Turbula mixer) to obtain a third substance / pharmaceutical premix It was. This is hereinafter referred to as Blend A.

  Final blend B is first premixed with an appropriate amount of blend A and compound X, and then (this blend A / compound X) premix is further blended A and shown in Table 1 and Tables 2 and 3 below. Obtained by blending in an appropriate weight ratio to obtain a final blend B containing magnesium stearate in the required amount. The amount of magnesium stearate in Tables 2 and 3 is the weight of magnesium stearate present, expressed as a percentage of the total composition. The final concentration of Compound X in the blend was 0.1% w / w (calculated based on the weight of free base drug present).

  For use in Example 2, the blend composition was transferred into a blister strip, or a type commonly used to provide dry powder for inhalation, and the blister strip was sealed in a conventional manner.

Table 1 shows the amount of various materials used in each blend.

  0.1 g of compound X in the form of cinnamate was used to obtain 0.1 g of the free base of compound X.

Decomposition conditions The blends prepared as described above were subjected to the accelerated decomposition conditions of an atmosphere controlled stable cabinet. In the table below, the conditions under which the blend was placed are indicated in terms of temperature and relative humidity%, for example 30/60 represents 30% relative humidity (RH) 60%. After the period shown in the table, the samples were analyzed for degradation products.

Blend purity analysis after being subjected to degradation conditions
LC analysis was performed on a Supelcosil ABZ + PLUS column (150 x 4.6 mm ID) [3 micron] containing 0.05% trifluoroacetic acid (solvent A) and 0.05% volume / volume (% v / v) trifluoroacetic acid The elution gradient employed was as follows: Time 0 = 90% solvent A, 10% solvent B; 40 minutes = 10% solvent A, 90% solvent B; 45 min Solvent A 90%, Solvent B 10%. The flow rate was 1 mL / min and the column temperature was 40 ° C. Detection was performed with HP1100 series detector model G1314A-VWD with 220nm UV. The area under the LC trace curve for all impurities was compared with the total area under the LC trace curve to obtain the (area / area)% shown in Tables 2 and 3.

result
Example 1 (Compound X / Lactose) Blend Containing Magnesium Stearate and Control

Example 2: Comparison of Compound X / Lactose Blend with 0.5%, 1.0% and 2.0% Magnesium Stearate Filled in Blister Strips and Control

Claims (19)

  Use of magnesium stearate to inhibit or reduce chemical interaction between an active ingredient substance and the carrier in a solid pharmaceutical formulation in which the active ingredient substance tends to chemically interact with the carrier.   Use of magnesium stearate to inhibit or reduce chemical degradation of an active ingredient substance in a solid pharmaceutical formulation comprising the active ingredient substance and a carrier, wherein the active ingredient substance tends to chemically interact with the carrier.   Use according to claim 1 or 2, wherein the carrier is a reducing sugar.   4. Use according to claim 3, wherein the carrier is lactose.   Use according to any one of claims 1 to 4, wherein the magnesium stearate is present in an amount of 0.1 to 20% w / w, based on the total weight of the composition.   Use according to any one of the preceding claims, wherein the active ingredient substance is present in an amount of 0.01 to 50% w / w based on the total weight of the composition. Wherein the pharmaceutical substance is intended to include groups _{Ar-CH (OH) -CH 2} -NH-R, use according to any one of claims 1 to 6. The medicinal substance is:
3- (4-{[6-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) hexyl] oxy} butyl) benzenesulfonamide;
3- (3-{[7-({(2R) -2-hydroxy-2- [4-hydroxy-3-hydroxymethyl) phenyl] ethyl} -amino) heptyl] oxy} propyl) benzenesulfonamide;
4-{(1R) -2-[(6- {2-[(2,6-dichlorobenzyl) oxy] ethoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol;
4-{(1R) -2-[(6- {4- [3- (cyclopentylsulfonyl) phenyl] butoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol;
Or use according to claim 7, selected from salts, solvates or physiologically acceptable derivatives thereof.   Use according to any one of claims 1 to 8, wherein the solid pharmaceutical formulation is for administration by inhalation.   Use according to any one of claims 1 to 9, wherein the solid pharmaceutical preparation comprises two or more active ingredient substances.   An inhalable solid pharmaceutical formulation comprising (a) an active ingredient substance that is likely to chemically interact with lactose, (b) a carrier, and (c) magnesium stearate.   12. The inhalable solid pharmaceutical formulation of claim 11, further comprising one or more of the features described in claims 3-10.   The active ingredient substance is 3- (4-{[6-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) hexyl] oxy} butyl) 13. An inhalable solid pharmaceutical formulation according to claim 11 or 12, which is benzenesulfonamide; or a salt, solvate or physiologically acceptable derivative thereof; and wherein the carrier is lactose.   A method of reducing or inhibiting a chemical interaction between an active ingredient substance susceptible to chemical interaction and a carrier, comprising mixing the active ingredient substance and the carrier with magnesium stearate.   A method for inhibiting chemical degradation of an active ingredient substance in a preparation comprising a carrier and an active ingredient substance, comprising mixing the active ingredient substance and the carrier with magnesium stearate.   16. A method according to claim 14 or 15, further comprising one or more of the features described in claims 3-10.   To manufacture pharmaceuticals for the treatment of asthma, chronic obstructive pulmonary disease (COPD), chronic or wheezing bronchitis, emphysema, respiratory infections, upper respiratory tract disease or rhinitis (including seasonal and allergic rhinitis) Use of an inhalable solid pharmaceutical formulation according to any one of claims 11-13.   Claims to a patient in need of such treatment for asthma, chronic obstructive pulmonary disease (COPD), chronic or wheezing bronchitis, emphysema, respiratory infection, upper respiratory tract disease, or rhinitis Item 14. A method comprising administering the inhalable solid pharmaceutical formulation of any one of Items 11-13.   A method of preparing a solid pharmaceutical formulation comprising mixing (a) an active ingredient substance that is likely to interact with a carrier, (b) a carrier, and (c) magnesium stearate in one or more steps.