KR20070017170A - The treatment of respiratory disease - Google Patents

Abstract

Glycopyrrolate or an analog thereof is useful for the treatment of bronchospasm or as a therapeutic agent.

Glycopyrrolate, bronchial spasms, asthma, COPD, allergic reactions

Description

Treatment of Respiratory Diseases {THE TREATMENT OF RESPIRATORY DISEASE}

The present invention relates to the treatment of respiratory diseases.

Glycopyrrolate has been known for many years as an effective antimuscarinic agent. It has been used in some symptoms and has been carried by many different routes. It is currently used as an injection prepared to reduce secretions during anesthesia and also as an oral agent for the treatment of gastric ulcers. One of the most important explanations for its use in airway disease was that in 1984 it proved to have a significant effect on bronchial dilatation. Since then, many studies have confirmed its potential usefulness.

Schroeckenstein et al ., J. Allergy Clin. Immunol., 1988; 82 (1): 115-119 discloses the use of glycopyrrolate in spray formulations for the treatment of asthma. Administration alone of the quantitative glycopyrrolate nebulizer achieved a bronchodilating effect over 12 hours.

Leckie et al ., Exp. Opin. Invest. Drugs, 2000; 9 (1): 3-23 is a treatment theory for chronic obstructive pulmonary disease (COPD). Glycopyrrolate has been mentioned as a possible drug therapy. However, there was no mention of the extent or duration of activity to exert its therapeutic effect.

Skorodin, Arch Intern. Med, 1993; 153: 814-828 discloses the use of glycopyrrolate in spray formulations for the treatment of asthma and COPD. In general, quaternary ammonium antiacetylcholinergic compounds are said to have a working time of 4 to 12 hours. Doses between 0.2 and 1.0 mg of glycopyrrolate were recommended at 6-12 hour intervals.

Walker et al ., Chest, 1987; 91 (1): 49-51 also disclosed the effect of inhalation of glycopyrrolate as an asthma treatment. In addition, the duration of effective treatment is shown to be up to 12 hours, although the most effective shows up to 8 hours.

WO97 / 39758 discloses a pharmaceutical composition for treating respiratory inflammation containing the antioxidant tyloxapol. Page 23 mentions the addition of glycopyrrolate as an additional component in the solution. There is no mention of the duration of activity of glycopyrrolate, and the proposed effective flux (200-1000 μg) was similar to that disclosed in the prior art.

WO01 / 76575 describes pharmaceutical compositions comprising antimuscarinic agents in pulmonary delivery, eg asthma, COPD or cystic fibrosis. Glycopyrrolate is a preferred agent. It can be formulated with magnesium stearate.

Since this composition is capable of exerting its therapeutic effect over a long period of time, patients may benefit from the alleviation of symptoms for longer periods than conventional antimuscarin therapy. Moreover, since patients can only require treatment regimens once a day, this often prevents the treatment from being missed and better medication delivery is expected.

Bronchial spasms are a frequent problem for people with airway diseases such as asthma or COPD. Immediate relief is required. Rescue agents are needed in acute bronchial spasms that can cause acute asthma, exacerbation of COPD or allergic reactions. Acute asthma development can be caused, for example, by exercise or environmental pollutants. The term "bronchospasm" thus includes idiopathic and non idiopathic diseases.

Summary of the Invention

As well as the benefits of the glycopyrrolate therapy described in WO01 / 76575, various unexpected benefits are found. For example, there is a strong and immediate onset of bronchial dilatation. In addition, the different doses of the drug appear essentially the same in terms of effectiveness without side effects. In addition, there are apparently no problems with antimuscarinic agents such as cardiac arrest. This makes the agent particularly suitable as a treatment or rescue agent for bronchial spasms.

The present invention utilizes antimuscarinic agents that are generally considered to exert their pharmaceutical effects over a period of less than 12 hours. "Pharmaceutical effect" relates to the ability of an agent to relieve symptoms of airway disease. This is elevated in the presence of the medicament, compared to that obtained in the absence of treatment with a measurement of FEV ₁ levels.

Antimuscarinic agents which can be used and which are structurally related to glycopyrrolate include compounds of the formula:

Where n is 0, 1 or 2;

R ₁ is phenyl or thiophenyl;

R ₂ is H, CH ₂ OH, phenyl, cyclohexyl, cyclopentyl or thiophenyl;

R ₃ is N ⁺ R ₅ R ₆ R ₇ Or a heterocycle of a 5 or 6 membered ring containing at least one N ⁺ R ₅ R ₆ group, or R ₅ or R ₆ is part of a ring as:

R ₄ is H or OH;

Each of R ₅ , R ₆ , R ₇ is methyl, ethyl, isopropyl or fluoroethyl; And

X ⁻ is a cation that is, for example, bromide or other halide, or methyl sulfate.

Examples of these drugs are benzylnium bromide, bebornium methyl sulfate, clindium bromide, flutropium bromide, glycopyrronium bromide, heteronium bromide, hexocyclium methyl sulfate, homotropin methyl bromide, ifprat Tropium bromide, mefenzolate bromide, oxyteponium bromide, oxyphenonium bromide, oxypyronium bromide, pentenate methobromide and pipefenzolate bromide.

In addition, the antimuscarinic agent is represented by the following formula;

Wherein n is 0, 1 or 2;

Each of R ₁ and R ₂ Phenyl or cyclohexyl;

R ₃ is a 5 or 6 membered heterocycle containing NR ₅ R ₆ or C≡CCH ₂ NR ₃ R ₄ or at least one NR ₅ group;

R ₄ is H or OH; And

Each of R ₅ , R ₆ is H, methyl, ethyl or propyl.

Examples of these drugs are benathizin, benaprizin, dicycloberine, oxybutynin, oxyphencycline and piperidolate.

Glycopyrrolate is preferred and the following description relates to glycopyrrolate formulations.

Glycopyrrolate has two stereocenters and therefore exists in the form of four isomers. Each of the individual isomers can be transported to optimize the effective effects of the drug, and these isomers reduce systemic exposure that causes systemic side effects.

Combinations of active isomers can be used, where the ratio of isomers is 1: 1, or less than 1: 1. Optionally, the combination of active isomers is non-racemate, or the combination ensures that the active isomers are delivered at different rates.

Salt forms or counter ionic preparations of glycopyrrolate are within the scope of the present invention, for example glycopyrronium bromide.

By the present invention, glycopyrrolate can be used as a therapeutic agent for the treatment of bronchial spasms. This utility may be apparent from the evidence presented below.

Patients to be treated in accordance with the present invention often suffer from complications or withstand other treatments. The present invention has utility in the treatment of certain patient groups, for example in patients with sensitivity due to cardiovascular, visual or mucosal complications.

Conventional formulation techniques can be used to achieve the desired release control properties. Importantly, the composition should have a duration of action of at least 12 hours, more preferably at least 15 hours or 18 hours, and most preferably at least 20 hours. This can be measured as follows by techniques known to those skilled in the art.

Controlled release formulations of glycopyrrolate are provided in a form suitable for delivery by inhalation. Apparatus and formulations suitable for delivery by inhalation are known to those skilled in the art. The composition may be prepared as a spray in liquid propellant for delivery, for example, in metered spray pressurized inhalers (PMDI's). Suitable propellants for use in PMDI are known to those skilled in the art and include CFC-12, HFA-134a, HFA-227, HCFC-22 (difluorochloromethane), HFA-152 (difluoroethane and isobutane) .

In a preferred embodiment of the invention, the composition is in dry powder form for delivery using a dry powder inhaler (DPI). Dry powder inhalers are known. The dry powder for use in the inhaler has a mass median aerodynamic diameter of less than 30 μm, preferably less than 20 μm, more preferably less than 10 μm. Particles having an aerodynamic diameter in the range of 5 to 0.5 μm can generally accumulate in the bronchioles of the respiratory tract, while smaller particles having an aerodynamic diameter in the range of 2 to 0.05 μm are likely to accumulate in the alveoli.

Since glycopyrrolate is provided in controlled release formulations, extremely low dosages are required. The inhaler may be supplied in a therapeutic package that supplies glycopyrrolate over an extended number of treatment days compared to a package with a similar dosage per pack, but two or three doses are required daily.

In a preferred embodiment of the invention, glycopyrrolate is formulated with a hydrophobic material to form microparticles suitable for inhalation. The fine particles may be in the above-described range. Any pharmaceutically acceptable hydrophobic material may be used to formulate the microparticles and suitable materials may be apparent to those skilled in the art. Preferred hydrophobic materials include solid state fatty acids such as oleic acid, lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid, or derivatives thereof (such as esters and salts). Specific examples of such materials include phosphatidylcholine, phosphatidylglycerol and other examples of natural and synthetic lung surfactants. Particularly preferred materials include stearates of metals, in particular magnesium stearate, which are allowed for transport via the lungs.

Hydrophobic materials are typically resistant to immediate dissolution upon administration but degrade over time to release the glycopyrrolate component.

The microparticles may also be combined with additional excipients to aid in transport and release. For example, with respect to dry powder formulations, the microparticles can be combined with additional large carrier particles that aid in flow from the dry powder inhaler into the lungs. Large carrier particles are known and include lactose particles having a mass median aerodynamic diameter of at least 40 μm. Optionally, the hydrophobic particulates can be uniformly dispersed in the carrier material. For example, the hydrophobic microparticles can be uniformly dispersed in the polysaccharide matrix with the total composition formulated as microparticles for direct delivery to the lungs. The polysaccharide acts as an additional barrier to the immediate release of the glycopyrrolate component. This is more conducive to the release control method. Suitable carrier materials may be apparent to those skilled in the art and include any pharmaceutically acceptable insoluble or soluble material including polysaccharides. An example of a suitable polysaccharide is xanthan gum.

The composition may also contain additional therapeutic agents as discrete components, ie as discrete particulates or in combination with glycopyrrolate in the particulates. In one embodiment, the therapeutic composition comprises the microparticles according to the invention together with the microparticles consisting of glycopyrrolate, ie without any hydrophobic material. This provides a composition with a fast-acting component and a release-modulating component and can provide effective relief for the patient quickly, with a long lasting effect. Fast-acting glycopyrrolate may be provided as additional particulates or may be dispersed with the hydrophobic particulates in the particles. For example, the polysaccharide particles can be formulated with hydrophobic particulates and fast-acting glycopyrrolate dispersed therein.

Controlled release formulations can be tested by methods known to those skilled in the art. Testing the formulation with respect to the release of glycopyrrolate in water can be used. The controlled release formulation will generally release 50% of glycopyrrolate by dissolution over a period of at least 10 minutes, preferably at least 20 minutes and most preferably at least 30 minutes in water. During dosing, the controlled release formulation may release glycopyrrolate over a period of at least 12 hours, preferably 15 hours, more preferably 20 hours.

Any suitable pharmaceutically effective drug used for the treatment of respiratory disease may also be coadministered with the glycopyrrolate composition of the present invention. For example, β ₂ -agents, such as salbutamol, salmeterol and pometoral, may be combined with the glycopyrrolate composition for combined administration. Additional antimuscarinic compounds may also be coadministered. For example, Ipratropium (eg, Ipratropium bromide) or Tiotropium can be administered. Isomers, salt forms or antiion preparations of antimuscarinic compounds are all within the scope of the present invention. These may be in their natural form or release controlling agents. Natural forms are preferred.

Additional therapies including steroids may also be administered in combination. Examples of suitable steroids include beclomethasone, dipropionate and fluticasone. Other suitable therapies include mucolytic agents, matrix metalloproteinase inhibitors, leukotrienes, antibiotics, antitumor drugs, peptides, vaccines, cough medicines, nicotine, PDE4 inhibitors, elastase inhibitors and sodium chromoglycates.

Combined therapy can provide the maximal effect on FEV-1 and lung capacity. Co-administration of other drugs with slowly releasing glycopyrrolate may also result in less side effects than co-administration with conventional glycopyrrolate formulations and may be less contraindicated because of the late onset of glycopyrrolate activity.

For example, since release control is practically given a constant plasma concentration, it is desirable that the formulation be used so that the highest plasma concentration for systemic exposure is lower than before.

The composition according to the invention can be calculated using conventional formulation techniques. In particular, spray-drying can be used to yield particulates comprising glycopyrrolate dispersed or suspended in materials that provide release control properties.

Grinding processes, such as jet grinding, also referred to as fluid energy grinding, can also be used for formulating therapeutic compositions. The production of fine particles by grinding can be accomplished using the prior art. The term “grinding” is used herein to refer to any mechanical method for applying or breaking a particle into fine particles by applying sufficient force to the particles of the active material. A wide range of grinding equipment and conditions is suitable for use in the preparation of the compositions of the present invention. For example, the selection of suitable grinding conditions, such as the strength and duration of grinding, depends on the skill of the person skilled in the art to provide the required degree of strength. Ball milling is the preferred method. Optionally, a high pressure homogenizer may be used where the fluid containing the particles passes through the valve at a high pressure which creates conditions of high shear and turbulence. Cavitation due to shear strength on particles, collisions between particles and machine surfaces or other particles, and acceleration of fluids can all cause fracture of the particles. Suitable homogenizers include EmulsiFlex high pressure homogenizers, Niro Soavi high pressure homogenizers and Microfluidics Microfluidiser. Grinding methods can be used to provide particulates having a mass median aerodynamic diameter as specified above. As above, it is preferable to grind the glycopyrrolate together with the hydrophobic material.

If necessary, the microparticles produced by the grinding step can be formulated with additional excipients to yield particles homogeneously dispersed with hydrophobic microparticles therein. This can be achieved by, for example, a spray-drying method which is merge-spray-dry. In this embodiment, the hydrophobic particulates are suspended in a solvent and co-spray-dried with a solution or suspension of the solution or additional excipients. The spray-drying process will yield particulates of the desired size, which may include hydrophobic particulates uniformly dispersed therein. Preferred additional excipients include polysaccharides. Additional pharmaceutically effective excipients may also be used. Optionally, the particulates produced by the grinding step can be coated with additives using a highly powerful dry mixing method. Such methods include those referred to as mechanofusion or hybridization.

The amount of active agent to be administered may be determined by common factors such as the nature and severity of the disease, the condition of the patient and the effectiveness of the agent itself. These factors can be readily determined by one skilled in the art. Controlled release formulations are used to maintain the effect of bronchodilation over an extended duration and to increase FEV levels. As a result of the next initial dose and subsequent doses, the FEV ₁ level will be maintained at a higher level than before the start of treatment. The single dose preferably provides sufficient active agent over at least 12 hours, preferably at least 15 hours or at least 18 hours, more preferably at least 20 hours so that glycopyrrolate can exert its pharmaceutical effect. The amount of glycopyrrolate released over this period will be sufficient to provide effective relief (bronchiectasis) of respiratory disease during this period. Measurement of bronchial dilatation can be performed by techniques known to those skilled in the art, including spirometry. This can be used to measure FEV ₁ over the dosing period. It is desirable to achieve an FEV ₁ value of at least 10%, preferably at least 20% and most preferably at least 30% of the expected normal value over the administration period. The amount of glycopyrrolate in a single dose is, for example, 0.02-5 mg, preferably less than 2 mg, most preferably less than 1 mg or about 1 mg. Higher or lower doses, eg less than 100 μg, may also be provided. With respect to the microparticles, glycopyrrolate can be present, for example, at least 20% by weight, preferably at least 40% by weight, more preferably at least 60% by weight.

The invention is illustrated in the following examples.

The accompanying drawings show the results obtained in a study describing the findings of the present invention.

1 is a graph showing the change in FEV1 upon administration with increased dose of placebo and sample to patients suffering from COPD.

FIG. 2 is a graph showing changes in FEV1 upon administration of placebo and AD 237 to patients suffering from asthma.

FIG. 3 is a graph showing changes in FEV1 upon dose administration of placebo and AD 237 to patients suffering from COPD.

4 is a graph showing the weighted average change in FEV1 with increasing AD 237 dose.

A mixture of glycopyrrolate and magnesium stearate, micronized to a mass ratio of 75:25 (total mass about 1 g), was placed on a ball mill of 100 g of 2 mm diameter stainless steel balls. The volume of the mill was approximately 58.8 ml. 5 ml of cyclohexane was added to wet the mixture. The mill was sealed and fixed in a Retsch S100 centrifuge. Thereafter, centrifugation was performed at 500 rpm for a total of 240 minutes. Some samples of wet powder (approximately 5-10 mg) were removed from the mill every 60 minutes. The sample was dried under vacuum at 37 ° C. in an oven.

The resulting formulation was tested. The method and results are reported below.

COPD Preliminary Research in-Research Criteria

Single dose, double blind, placebo-controlled dose escalation

Duration of treatment (4 days): Randomized in order of 60 → 120 → 240 → 480 μg with placebo

8 patients in total (1 dropout)

COPD (FEV1; FVC <70%; 45% ≤FEV ₁ <predicted 70%)

≤12% reaction with β ₂ agonists

Perform FEV ₁ over 24 hours

5-7 days interruption between treatments

The results are shown in FIG. 1; See also the following table.

Preliminary Study in Asthma-Research Criteria

patient:

    Mild to moderate asthma (FEV1≥55%)

     Increase ≥15% of FEV1 and 150ml after Atrovent 80μg

Part 1: single dose dose tolerance stage

        8 patients, 480 μg for 2 patients per dose group

Part 2: One dose of 480 μg AD237 in FEV1 compared to placebo

        6 patients

        Respond to atrovent: bronchial dilatation of at least 15% 30 minutes after administration

        FEV1 measured after 32 hours

        5-7 days interruption between treatments

The results are shown in FIG. 2; See also Table 1.

Table 1

Change from placebo (milliliters) Dose (μg) 60 (N = 5) 120 (N = 6) 240 (N = 5) 480 (N = 5) COPD Top fev ₁ 460 150 234 226 Lowest FEV ₁ 180 4 124 186 asthma Top fev ₁ n / a n / a n / a 430 Lowest FEV ₁ n / a n / a n / a 375

These preliminary results provided great encouragement for conducting formal Phase IIa studies.

Step IIa COPD  Dose Range Study

Purpose: When patients with COPD take 200-400㎍,

                 To investigate dose- and time-response

Number of centers: 5 (UK and Germany)

Number of patients: 40

Project Study: Placebo-control unit with randomized placebo

                 Single Dose Dose Study

Dosage: AD 237 20, 125, 250, 400 μg and placebo

Formulation: Optimized Dry Powder PowderHale® Formulation (Improved Delivery)

Primary end: weighted average change in FEV ₁ (0 to 24 hours)

include

Diagnosis of COPD: Smoking: FEV ₁ 40-80% Predicted FEV1 / FVC ratio <70%

Reversible airway: FEV ₁ increase ≥12% and 150 ml after ipratropium

No long-acting antiacetylcholine drugs

exclusion

Susceptibility of Peripheral Side Effects of Anti-Muscarinic Agents

Evidence of asthma

Unstable disease (requires URTI at last 6 weeks, oxygen therapy)

Pregnant

Valid data is shown in FIG. 3; These represent a significant effect on FEV ₁ and a sustained 24 hour duration of response. Dose reactions are shown in FIG. 4.

Maesen et al , Eur. Resp. As described by J. (1995) 8: 1506-1513, a comparison was made between 125 μg and 20 μg spriva. This is shown in Table 2 below.

TABLE 2

Adjusted average (ml) 125 µg Spiraba 20µg Best improvement at FEV ₁ 397 325 Average improvement in FEV1 after 24 hours 122 97 Lowest FEV ₁ 45 21

Phase IIa Stability

No serious side effects

3 severe side effects

Only one may be involved in treatment (headache)

The most frequently reported side effects were headache (20/86 report); Shortness of breath (5/86); Sore throat (4/86) and wheeze (3/86).

Slight, temporary decrease in heart rate after taking

There is no report of dry mouth

Claims (14)

Use of glycopyrrolate or an analog thereof for the manufacture or rescue of a medicament for the treatment of bronchial spasms. 2. Use according to claim 1, wherein said medicament is a dry powder composition for lung delivery comprising microparticles of glycopyrrolate. 3. Use according to claim 2, wherein the particulates have a mass median aerodynamic diameter of less than 30 μm. 4. Use according to claim 3, wherein the mass median aerodynamic diameter is from 0.05 to 5 mu m. The use according to any one of claims 1 to 4, wherein the medicament additionally comprises large carrier particles. 6. The use according to claim 5, wherein the large carrier particles are lactose particles having a mass median aerodynamic diameter of at least 90 μm. Use according to any of the preceding claims, wherein the medicament additionally comprises a hydrophobic substance. 8. Use according to claim 7, wherein the hydrophobic material is magnesium stearate. The patient of claim 1, wherein the patient is also a β 2 -agonist, a steroid, a mucolytic agent, an MMP inhibitor, leukotriene, an antibiotic, an anti-tumor drug, a peptide, a vaccine, a cough medicine, nicotine, sodium chromogly Use with a therapeutic agent selected from Kate, PDR4 inhibitors and elastase inhibitors. Use according to any one of the preceding claims, wherein the medicament is in the form of a dosage unit comprising less than 5 mg glycopyrrolate. Use according to claim 10, wherein the dosage unit comprises less than 1 mg of glycopyrrolate. Use according to any one of claims 1 to 11, wherein the medicament is for use as a rescue medicament following acute asthma. Use according to any one of claims 1 to 11, wherein the medicament is for use as a rescue medicament due to exacerbation of COPD. Use according to any one of claims 1 to 11, wherein the medicament is for use as a rescue medicament following an allergic reaction.

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