DRY POWDER FORMULATION COMPRISING A PHARMACEUTICAL

COMBINATION

DESCRIPTION

The present invention is related to a pharmaceutical composition comprising formoterol, mometasone, tiotropium and/or pharmaceutically acceptable derivatives thereof, and the use of this composition in the treatment of respiratory diseases particularly in asthma, allergic rhinitis and chronic obstructive pulmonary diseases (COPD).

Airways, in other words bronchia, are the channels which function to distribute the inhaled air into the lung tissues. In the case of respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD), stimulants such as allergen, infection, good and bad smell, smoke, genetic factors and exercise cause contractions in the airway muscles (bronchoconstruction) and/or excessive secretion in glands and results in contractions in the airway. Hence, respiration gets more difficult as the inhaled air cannot be exhaled.

Corticosteroids which are used in the treatment of asthma and COPD are synthetic and strong anti-inflammatory drugs that are similar to natural corticosteroid hormones produced by adrenal glands. They prevent both the transcription of the inflammatory gene and the activation of the anti-inflammatory gene. In addition to this, they increase the transcription of β ₂ receptors. Furthermore, corticosteroids prevent the tolerance that develops after a long- term application of β ₂ agonists. Beclomathasone, budesonide, ciclesonide, flunisolide, fluticasone are among the steroids that are used for the treatment of respiratory diseases.

Corticosteroids are not preferred in acute asthma crises as they do not have rapid onset of action. Since inhaled corticosteroids may prevent growth in children, they are advised to be used in the lowest possible amount. Long-term use of corticosteroids may cause cataract and glaucoma. In addition, they may cause some serious side-effects such as osteoporosis, high cholesterol, edema, encepholalgia, weight gain, insomnia and some skin problems. β ₂ adrenergic agonists which are used in the treatment of respiratory diseases such as asthma and COPD affect the muscles around the air vessels by activating β ₂ adrenergic receptors. They reduce or eliminate bronchospasm. Bronchodilator β ₂ ^οηΪ8ί8 are categorized into two groups as long-acting and short-acting. Short-acting beta-agonists such as salbutamol, levosalbutamol, prosaterol, fenoterol, terbutaline, pirbuterol, metoproterenol, bitolterol mesilate have a rather rapid onset of action such as 3-5 minutes and their duration of action is of 4-6 hours. As they have a rapid onset of action, they are given as relaxant but they should be taken very often since they have a short duration of action. Long-acting β ₂ agonists have a slower onset of action compared to the other group but their duration of action is of 12 hours. Salmeterol, formoterol, bambuterol and clenbuterol can be given as examples to long-acting β ₂ agonists. Long-acting p ₂ -agonists are often used in the treatment of patients who present asthma symptoms at nights and in the treatment of asthma stimulated by exercise. β ₂ agonists are known as the most effective agent in order to eliminate acute asthma symptoms. One of the most important factors for their being used as symptomatolytic is their onset of action. Some long-acting β ₂ agonists can have the onset of action of short acting β ₂ agonists when used at specific doses. β ₂ agonists affect the muscles above the air vessels. However, they might affect the muscles around the heart and the bones. In the case that they affect the heart muscles, acceleration of heartbeat and palpitation might be observed. In 2005, US Food and Drug Administration (FDA) revealed that many long-acting drugs increase wheezing symptom in patients. Following this, in a study carried out by Cornell and Stanford Universities, it was found out that regular intake of β-agonists in the treatment of COPD increases health problems resulting from respiratory tract.

Anticholinergics are the other active agents which are utilized in the treatment of respiratory diseases. Anticholinergics influence large airways including the muscles above bronchia, while β ₂ agonists influence small airways, in other words bronchioles. Anticholinergics such as β ₂ agonists are categorized into two groups as long-acting and short-acting. . Short-acting anticholinergics including ipratropium bromide and oxitropium bromide have an onset of action of 15 minutes and their duration of action is 6-8 hours. The long-acting anticholinergic agent is tiotropium. Tiotropium has an onset of action of 20 minutes and its duration of action is 24 hours. Thus, it is enough to take it once a day. Side effects of anticholinergics are weaker than the side effects of β ₂ agonists.

The use of combination drugs in the treatment of respiratory diseases such as asthma and COPD is very effective particularly in decreasing asthma attacks. It is possible that the severity or occurrence possibility of the abovementioned side effects decreases as the active substances that are used in combinations are more effective at lower doses compared to the active substances used alone. However, decreasing the side effects that arise from the active agents is not sufficient to provide effective treatment for respiratory diseases. The medicaments used in the formulations should be selected in a way to give the best combination and furthermore, they should be in the most stable form. Moreover, the compositions comprising them should be formulated in such a way that the composition is stable and also it reaches to the target area in the most efficient way.

The inventor has surprisingly found that unexpected therapeutic benefits are obtained through the use of the combination comprising of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate together for simultaneous or sequential administration in the prevention or treatment of respiratory diseases.

It was seen that a combination comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate provides the most stable and therapeutically beneficial combination for simultaneous or sequential administration in the prevention or treatment of respiratory diseases. Preferably, a composition comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate is administered simultaneously. Formoterol fumarate used in the formulation is preferably in dihydrate form.

In another aspect, said composition consists of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate, mometasone furoate and lactose. In another aspect, tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate, mometasone furoate are preferably combined in a single dosage form.

Furthermore, the amount of the active agents used in the composition is carefully adjusted in order to prevent the side effects that might arise from these agents and it was seen that minimum side effects are observed when tiotropium bromide with water content less than or equal to 2.5%: formoterol fumarate: mometasone furoate ratio in the composition is in the range of 1 : 0,1 : 5 to 1 : 3 : 40 by weight. Furthermore, it was seen that in the formulation, which is constituted with active agents in amounts that has the ratio in the range of 1 : 0,1 : 5 to 1 : 3 : 40 , the adhesive force between the particles is less and hence, the amount of inhaled particles and efficacy of the formulation increases. Accordingly, the present invention provides a combined drug preparation comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate in the amounts which are in the range of 1 : 0,1 : 5 to 1 : 3 : 40 for simultaneous or sequential administration in the prevention or treatment of respiratory diseases such as asthma and chronic obstructive pulmonary diseases (COPD).

According to another aspect, the present invention provides an effective inhalation of the drug comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate.

The drug pertaining to the present invention is preferred to be administered by the inhalation route as it a) has a more rapid onset of action compared to the administration via oral or parenteral routes b) enables the use at lower doses c) minimizes the side effects. According to another aspect, the present invention provides simultaneous or sequential inhalation of the drug comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate by the inhalation route.

According to another aspect, the present invention provides the transmission of the drug comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate via single or multi dose inhalers.

The drug comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate can be in dry powder form; they can be formulated with propellant gases to give aerosol formulations or they can be formulated with solvents to give nebulizer formulations. The inventors have found that the best way to transfer the medicament comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate is using this medicament combination in dry powder form.

In this way, the components maintain their stability and furthermore, the medicament is in a stable form and is easily used by the patients. In order to ensure effective absorption of the active agents into the lung tissue, the particle size of the agents should be adjusted. Although large particle size provides ease in manufacturing the dry powder, it may accumulate in throat and lead to insufficient intake of the medicament. Very fine particles, on the other hand, may reach the lungs. However, they might not have a good flow property which causes problems in providing dose accuracy in turn. To prevent these problems, the active agents should have an optimum average particle size. The inventors have found that tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate, mometasone furoate having a mean particle size in the range of 1.5 to 4.5 μηι reaches the lungs effectively and also no problems related to flow properties of the dry powder are observed.

In one aspect, the present invention provides a medicament composition comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate in dry powder form wherein the mean particle size of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate is in the range of 1.5 to 4.5 μηι and wherein said active agents are present in the composition with the ratio of 1 : 0,1 : 5 to 1 : 3 : 40 respectively and said composition can be simultaneously or sequentially administered in the prevention or treatment of respiratory diseases.

The term "mean particle size" refers to particles wherein the particle size of 50% of the total number of particles is less than the average particle size. According to the present invention, the drug comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate may also contain effective amounts of excipients and/or additional agents apart from active agents.

According to the present invention, the dry powder formulation comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate is transmitted to the patient in dry powder form. Said dry powder formulations also contain some physiologically acceptable excipients along with the active agent. These excipients can be monosaccharides (glucose, etc.), disaccharides (lactose, saccharose, maltose, etc.), oligosaccharides and polysaccharide (dextran, etc.), polyalcohols (sorbitol, mannitol, xylitol, etc.), salts (sodium chloride, calcium carbonate, etc.) or a mixture thereof. The inventors have found that in compositions according to present invention, in other words in compositions comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate in dry powder form wherein the mean particle size of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate is in the range of 1.5 to 4.5 μηι and wherein said active agents are present in the composition with the ratio of 1 : 0,1 : 5 to 1 : 3 : 40 respectively, using lactose as the one and only carrier provides optimum homogeneity and flow properties to the dry powder and therefore, dose accuracy is maintained.

It was also seen that the mean particle size of the carrier plays an important role in delivery of the medicament to the target area, i.e. lungs, effectively in the compositions pertaining to the present invention. It was found that the adhesive forces between the lactose particles and the active agents having a mean particle size in the range of 1.5 to 4.5 μιη are minimized and thus an effective inhalation of the active agents takes place, when lactose having a mean particle size less than or equal to 100 μιη is used in compositions comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate in dry powder form wherein the mean particle size of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate is in the range of 1.5 to 4.5 μπι and wherein said active agents are present in the composition with the ratio of 1 : 0,1 : 5 to 1 : 3 : 40 respectively.

In another aspect, the present invention provides a composition comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate in dry powder form wherein;

• the mean particle size of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate is in the range of 1.5 to 4.5 μιη and

• said active agents are present in the composition with the ratio of 1 : 0,1 : 5 to 1 : 3 : 40 respectively and

• lactose which has a mean particle size less than 100 μιη is used as carrier.

Lactose which has a mean particle size less than 100 μπι is preferably used as a mixture of particles having two different mean particle sizes. Accordingly, lactose which has a mean particle size less than 100 μηι can be present as a mixture of particles having a mean particle size less than 10 μπι (fine) and particles having a mean particle size in the range of 10 μιη to 100 μηι (coarse). The inventors have observed that when lactose which has two different mean particle sizes is used, the adhesive force between the active agents and lactose is even less.

The weight ratio of lactose which has a mean particle size less than 10 μηι (fine) to lactose which has a mean particle size in the range of 10 μιη to 100 μιη (coarse) is in the range of 1 :1 to 1 :25, preferably in the range of 1 : 1 to 1 : 10, more preferably in the range of 1 : 1 ,5 to 1 : 5. According to the present invention, the amount of pharmaceutically acceptable carrier is preferably in the range of 0-50 mg.

According to another aspect, the present invention provides a method to transmit the drug combination comprising tiotropium, formoterol and mometasone and/or pharmaceutically acceptable derivatives thereof via a dry powder inhaler in which the drug is stored in peelable blister packs, capsules or a reservoir for use in the treatment of patients suffering from respiratory diseases.

In the inhalation devices which are designed to transmit dry powder drugs, an effective amount of the dry powder drug is prepared for inhalation when the device is triggered. In order to prepare the dry powder formulation stored in capsules, the supplementary components in the device provides the capsule to open or be pierced when the device is triggered and the dry powder formulation is prepared for inhalation. After the inhalation is completed, the empty capsule is ejected from the device and a new capsule is placed immediately before the following inhalation takes place. According to the present invention, the capsule can be made of a substance chosen from a group comprising gelatine, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers as well as consisting intertwined upper and lower compartments.

In the case that the capsule used in the present invention is made of cellulose or its derivatives, the capsule material can be selected from, but not limited to, a group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose.

In the case that the capsule used in the present invention is synthetic polymer, the capsule material can be selected from, but not limited to, a group comprising polyethylene, polyetheleneteraphtalate, polycarbonate or polypropylene.

In the case that the capsule material used in the present invention is gelatine, additional agents such as polyethylene glycol, sorbitol, glycerol, propylene glycol, polyethylene oxide - polypropylene oxide block copolymers and/or other polyalcohols or polyethers at different molecular weights can be added into it. The dry powder drug pertaining to the present invention can also be stored in blister packs apart from reservoirs and capsules. Blister packs are comprised of orderly placed blisters each of which contains minimally one dose of the dry powder drug. Blister packs can be pierced or peeled to be opened according to the device design. However, peelable blister packs are preferred according to the present invention. When the device is triggered, the blister pack or one of the blisters in the pack is pierced or peeled and the drug in dry powder form is prepared for inhalation.

The cavity volume of the blisters pertaining to the present invention, which are placed side by side in an order and which provide to transmit and store the dry powder drug in blister pack is in the range of 17-30 mm , preferably in the range of 18-23 mm ' most preferably in the range of 19-21 mm ^3'

The cavity volume of the blisters pertaining to the present invention, which provide to transmit and store the dry powder drug comprising tiotropium bromide having water content less than 2.5%, formoterol fumarate and mometasone furoate is in the range of 17-30 mm , preferably in the range of 18-23 mm ' most preferably in the range of 19-21 mm and each blister cavity having the volume described above is filled up to 25-100 %, preferably up to 70-100 %, most preferably up to 90-100 % of said volume in order to meet the specified needs for an effective inhalation. The lid and the base sheets of said blister pack are closed very tightly by any suitable method to provide impermeability. According to the present invention, the lid and the base sheet constituting the blister package consist of several layers. Polymeric layers, aluminum foil and preferably Aclar® fluoropoylmer film are among the layers that form the lid and the base sheet.

Aclar® fluoropolymer film is a polymeric film which is used in blister packs and provides excellent moisture barrier. This chemically inert polymeric film does not cause any change in the taste of the formulation when it is in contact with the dry powder formulation. In addition, it easily constitutes a layered structure with the other polymeric layers which are composed of various polymers. It is appropriate to be transacted with heat.

In order to decrease the gas and moisture permeability of the layer, preferably desiccant agents are added to the polymeric layers to preserve the stability of the dry powder formulation stored in blisters that are arranged in an order on blister strips. Silica gel, zeolite, alumina, bauxite, anhydrous calcium sulfate, activated carbon and clay which have the property of water absorption can be given as examples to desiccant agents.

As it is common to use aluminum in lid and base sheets of high protection blister packs, aluminum is used both in the lid and the base sheets of the blister pack of the present invention in order to provide high moisture and gas protection. These aluminum foils must be thick enough to provide the desired protection for the stability of the moisture sensitive dry powder formulation stored in the blister cavity. Due to this reason, the thickness of the aluminum foil that is used in the lid and the base sheets of the blister pack is chosen to be in the range of 10 to 40 μπι, preferably of 15 to 30 μηι. The polymeric layers in the lid and the base sheets of the blister pack mentioned in the present invention are made from the same or different polymers. The thickness of these polymeric layers varies according to the type of the polymeric substance used and its properties. Therefore, the thickness of the polymeric layer varies in the range of 15-60 μπι, preferably of 20-35 μηι depending on the type of the polymer used. The inside layer of the blister cavity of the said blister pack which is in contact with the dry powder formulation is a polymeric layer because of the fact that some of the dry powder formulation sticks onto the inside layer of the blister cavity due to the porous structure of aluminum foil and electrostatic forces, and hence causes uncontrolled dosing.

According to the present invention, the polymers used to form the polymeric layers are preferably selected from a group comprising thermo-plastic polymers such as polyethylene, polypropylene, polystyrene, polyolefin, polyamide, polyvinyl chloride, polyurethane or other synthetic polymers.

In addition, the blisters which constitute the blister pack pertaining to the present invention can be in any shape as long as they have the properties described above. According to the present invention, tiotropium bromide with water content less than or equal to 2.5% can be in crystal form and/or amorphous form or combination thereof. According to the present invention, formoterol fumarate can be in the form of its solvates, hydrates enantiomers, diastereomers, racemates and/or in crystal form and/or amorphous form and/or a combination thereof.

According to the present invention, mometasone furoate can be in the form of its solvates, hydrates, enantiomers or diastereoisomers, racemates and/or in crystal form and/or in amorphous forms and/or a combination thereof.

According to the present invention, the amount of tiotropium bromide having water content less than or equal to 2.5% included in the drug formulation comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate is in the range of 1-40 μg, preferably 1-30 μg per dose.

According to the present invention, the amount of formoterol fumarate included in the drug formulation comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate is in the range of 1-30 μg, preferably 1-20 μg per dose. According to the present invention, the amount of mometasone furoate included in the drug formulation comprising tiotropium bromide with water content less than 2.5%, formoterol fumarate and mometasone furoate is in the range of 50-600 μg, preferably 150-500 μg per dose.

The pharmaceutical composition mentioned in the present invention which comprises tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate in dry powder form wherein;

• the particle size of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate is in the range of 1.5 to 4.5 μηι and

• said active agents are present in the composition with the ratio of 1 : 0,1 : 5 to 1 : 3 : 40 respectively and

· lactose which has a mean particle size less than 100 μπι is used as carrier can be used in the treatment of many respiratory diseases such as asthma, chronic obstructive pulmonary disorder (COPD) and allergic rhinitis. Accordingly, the respiratory diseases include, but not restricted to, allergic or non-allergic asthma at any phases, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airways hyperactivity, bronchiectasis, chronic obstructive pulmonary, airways or lung diseases (COPD, COAD or .COLD) including emphysema and chronic bronchitis, pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. The treatment of said diseases may be prophylactic or symptomatic. In addition, the pharmaceutical composition pertaining to the present invention is used especially for the symptomatic treatment of asthma, allergic rhinitis and COPD.

A method for preparing the pharmaceutical composition according to the present invention comprises micronizing the tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate, preferably by air jet mill, mixing the micronized tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and mometasone furoate with lactose, then blending the composition to obtain a homogeneous dry powder mixture, and then filling the obtained dry powder mixture into capsules or blisters.

The combination of the pharmaceutical composition pertaining to the present invention can be explained with, but not restricted to, the examples given below.

Example 1 So as to be used in a multiple dose inhaler, a dry powder drug formulation which is appropriate to be stored in blisters comprises 18 parts of tiotropium bromide with water content less than or equal to 2.5% 12 parts of formoterol fumarate, 100 parts of mometasone furoate having a mean particle size of 1.5-4.5 μηι all of which are micronized in air jet mill and 10000 parts of lactose as carrier which has a particle diameter less than 100 μηι. The active substance tiotropium bromide with water content less than or equal to 2.5% given in this example includes its pharmaceutically acceptable amorphous and crystal forms thereof; formoterol fumarate includes its all pharmaceutically acceptable racemates, enantiomers or diastereomers, solvates, hydrates and/or amorphous and crystal forms and mometasone furoate includes its all pharmaceutically acceptable solvates, hydrates and/or enantiomers and/or amorphous and crystal forms. Lactose in this example can optionally be added in a higher or lower amount.

The amounts in Example 1 can be replaced by the amounts given in the table below and the example can be repeated. Amount of Amount of

Amount of

Tiotropium Formoterol

Example Mometasone Lactose (Parts)

Bromide Fumarate

Furoate (Parts)

(Parts) (Parts)

2 21 4,5 100 16960

3 21 4,5 200 15896

4 21 4,5 300 12000

5 21 4,5 400 11522

6 12 4,5 100 10230

7 12 4,5 200 14780

8 12 4,5 300 15230

9 12 4,5 400 16930

10 21 6 100 18236

11 21 6 200 9628

12 21 6 300 9888

13 21 6 400 10236

14 12 6 100 9966

15 12 6 200 11223

16 12 6 300 17852

17 12 6 400 18520

18 12 6 500 19630

19 21 9 100 21003

20 21 9 200 13540

21 21 9 300 12874

22 21 9 400 13695

23 12 12 500 20360

24 12 15 220 14800

25 12 15 330 15600

26 12 15 110 19850

27 12 15 550 14750

28 12 15 440 12500

29 15 15 220 13250

30 15 15 330 13650 31 15 15 440 14350

32 15 15 550 12680

33 15 15 110 13690

34 21 3 110 15996

35 21 3 220 11560

36 21 3 330 10080

37 21 3 400 12630

38 21 3 500 12222

Example 39

A dry powder formulation which is appropriate for a gelatine capsule used in a capsule inhaler comprises 18 parts of tiotropium bromide with water content less than or equal to 2.5%, 200 parts of formoterol fumarate, 200 parts of mometasone furoate having a mean particle size of 1,5-4,5 μπι all of which are micronized in air jet mill, and 5750 parts of lactose as carrier which has a particle diameter less than 100 μιη.

The active agent tiotropium bromide with water content less than 2.5% given in this example includes its all pharmaceutically acceptable amorphous and/or crystal forms thereof; formoterol fumarate includes its all pharmaceutically acceptable racemates, enantiomers or diastereomers, solvates, hydrates and/or amorphous and/or crystal forms and mometasone furoate includes its all pharmaceutically acceptable solvates, hydrates and/or enantiomers, and/or amorphous and/or crystal forms. Lactose given in this example can optionally be added more or less. The capsule in this example is made of gelatin but it can optionally be made of chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers.

The combination of the pharmaceutical composition pertaining to the present invention can be explained with, but not restricted to, the examples given below.

The amounts used in Example 20 can be replaced by the amounts given in the table below and the example can be repeated. Amount of Amount of

Amount of

Tiotropium Formoterole

Example Mometasone Lactose (Parts)

Bromide Fumarate

Furoate (Parts)

(Parts) (Parts)

39 21 4,5 100 4500

40 21 4,5 200 5750

41 21 4,5 300 3560

42 21 4,5 400 3900

43 1 1 4,5 100 3850

44 11 4,5 200 5500

45 11 4,5 300 5600

46 11 4,5 400 5250

47 21 6 100 4400

48 21 6 200 4600

49 21 6 300 4630

50 21 6 400 4890

51 11 6 100 5010

52 1 1 6 200 5020

53 11 6 300 2760

54 11 6 400 4250

55 11 6 500 4360

56 21 9 100 4750

57 21 9 200 5200

58 21 9 300 5300

59 21 9 400 5600

60 11 9 100 5980

61 11 9 250 4500

62 11 9 350 4680

63 11 9 550 4890

64 11 9 400 4250

65 11 15 220 6130

66 11 15 330 6250

67 11 15 110 5460 68 11 15 550 4500

69 11 15 440 5500

70 15 15 220 4750

71 15 15 330 5250

72 15 15 440 6100

73 15 15 550 3999

74 15 15 110 5020

75 21 3 110 5300

76 21 3 220 5600

77 21 3 330 5980

78 21 3 400 4500

79 21 3 500 4680

80 12 10 110 4890

81 12 10 220 4500

82 12 10 330 5750

83 12 10 400 3560

84 12 10 200 3900

85 12 10 300 3850

86 12 10 110 5500

87 20 8 150 5600

88 20 8 250 5250

89 20 8 350 4400

90 20 8 200 4600

91 20 8 400 4630

92 20 8 200 5980

93 21 ^{1 1} 440 4500

94 21 ^{1 1} 200 4680

95 21 ^{1 1} 400 4890

96 21 ^{1 1} 220 4250

97 21 ^{1 1} 440 4360

98 21 ^{1 1} 330 4850

99 21 ^{1 1} 550 3690