Pharmaceutical compositions for glucocorticoid replacement therapy

Abstract

The invention relates to glucocorticoid replacement therapy and provides pharmaceutical compositions and kits designed to deliver one or more glucocorticoids to a subject in need thereon in a manner that results in serum levels of the glucocorticoid that essentially mimic that of a healthy subject for a clinically relevant period of time. The pharmaceutical compositions and kits are prepared in such a way that a first part of one or more glucocorticoids is substantially immediately released and a second part of one or more glucocorticoids is released over an extended period of time of at least about 8 hours. The invention also relates to a method for treating diseases requiring glucocorticoid treatment such as in subjects having a glucocorticoid deficiency disorder.

Claims

1. A method for once daily treatment of a glucocorticoid deficiency disorder in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a coated tablet dosage form once daily in the morning, said coated tablet dosage form comprising: (a) an extended release tablet core and an immediate release coating surrounding said extended release tablet core; and (b) a total dose of about 1 mg to about 80 mg of hydrocortisone; wherein said extended release tablet core comprises hydrocortisone, the amount of hydrocortisone present in said extended release tablet core is about 60% to 80% of the total amount of hydrocortisone present in said coated tablet dosage form and is released over an extended period of time of at least 8 hours, wherein said immediate release coating comprises hydrocortisone and the amount of hydrocortisone present in said immediate release coating is about 20% to 40% of the total amount of hydrocortisone in said coated tablet dosage form.

2. The method according to claim 1, wherein a hydrocortisone serum level of at least about 200 nmol/l is obtained within 45 min after administration of said coated tablet dosage form to said patient.

3. The method according to claim 1, wherein a hydrocortisone serum level of at least about 200 nmol/l is obtained within 30 min after administration of said coated tablet dosage form to said patient.

4. The method according to claim 1, wherein a hydrocortisone serum level in a range of from about 400 to about 1000 nmol/l is obtained 2 hours after administration of said coated tablet dosage form to said patient.

5. The method according to claim 1, wherein a hydrocortisone serum level in a range from about 200 to about 600 nmol/l is obtained 6 hours after administration of said coated tablet dosage form to said patient.

6. The method according to claim 5, wherein the hydrocortisone serum level obtained is in a range of from about 200 to about 400 nmol/l.

7. The method according to claim 1, wherein a hydrocortisone serum level in a range of from about 50 to about 300 nmol/l is obtained 10 hours after administration of said coated tablet dosage form to said patient.

8. The method according to claim 1, wherein a hydrocortisone serum level in a range of from about 50 to about 200 nmol/l is obtained 14 hours after administration of said coated tablet dosage form to said patient.

9. The method according to claim 1, wherein the coated tablet dosage form is administered to said patient at wake-up in the morning between about 4 am and noon.

10. The method according to claim 9, wherein the coated tablet dosage form is administered to said patient in a fasted state.

11. The method according to claim 1, wherein a hydrocortisone serum level is obtained, in a time period corresponding to about 0.5 hours to about 7 hours after administration of the coated tablet dosage form to said patient, which substantially mimics the serum level of cortisol of a healthy subject in the morning from 6 am to noon.

12. The method according to claim 1, wherein a 3 hour substantially hydrocortisone-free serum level is obtained within a time period from about 10 pm to about 6 am.

13. The method according to claim 1, wherein at least 50% of the hydrocortisone in the immediate release coating is released within the first 30 min of an in vitro dissolution test according to USP employing USP Dissolution Apparatus No. 2. (paddle); 50 rpm and simulated intestinal fluid without enzymes as dissolution medium.

14. The method according to claim 1, wherein the hydrocortisone of the extended release tablet core is released over an extended period of time of at least 10 hours as determined by an in vitro dissolution test according to USP employing USP Dissolution Apparatus No. 2. (paddle); 50 rpm and simulated intestinal fluid without enzymes as dissolution medium.

15. The method according to claim 1, wherein at least 50% of the total hydrocortisone in the coated tablet dosage form is released within 10 hours of an in vitro dissolution test according to USP employing USP Dissolution Apparatus No. 2. (paddle); 50 rpm and simulated intestinal fluid without enzymes as dissolution medium.

16. The method according to claim 1, wherein said glucocorticoid deficiency disorder is adrenal insufficiency.

17. The method according to claim 1, wherein said extended release tablet core further comprises one or more excipients selected from the group consisting of hydroxypropylmethylcellulose, microcrystalline cellulose, pregelatinized starch, colloidal silica, and magnesium stearate.

18. The method according to claim 1, wherein said immediate release coating further comprises one or more coating materials selected from the group consisting of hydroxypropylmethylcellulose, polyvinyl alcohol, polyethylene glycol, titanium dioxide and talc.

19. The method according to claim 1, wherein the coated tablet dosage form is for oral administration.

20. The method according to claim 1, wherein the coated tablet dosage form is administered to said patient at wake-up in the morning between about 6 am and 8 am.

21. The method according to claim 1, wherein the coated tablet dosage form contains about 5 mg to about 50 mg hydrocortisone.

22. The method according to claim 1, wherein the coated tablet dosage form contains 20 mg hydrocortisone.

23. The method according to claim 1, wherein the coated tablet dosage form contains 5 mg hydrocortisone.

Description

LEGENDS TO FIGURES

(1) FIG. 1 shows results from Example 6. In vivo plasma profile. Extended release tablet, 7 mm diameter, medium compression force, 20 mg hydrocortisone, oral administration. Subject has the endogenous glucocorticoid secretion suppressed by synthetic glucocorticoids.

(2) FIG. 2 shows results from Example 6. Dissolution profile of IR-ER tablet

(3) FIG. 3 shows results from Example 11. In vivo plasma profile. Extended release tablet, 7 mm diameter, medium compression force, 20 mg hydrocortisone, oral administration and mucoadhesive thin-layer film 10 mg hydrocortisone, buccal administration. Subject has the endogenous glucocorticoid secretion suppressed by synthetic glucocorticoids.

(4) FIG. 4 shows results from Example 12. In vivo plasma profile. Extended release tablet, 7 mm diameter, medium compression force, 20 mg hydrocortisone, oral administration and solution of 10 mg hydrocortisone in 200 ml of water, oral administration. Subject has the endogenous glucocorticoid secretion suppressed by synthetic glucocorticoids

(5) FIG. 5 shows results from Example 18. The plasma concentration-time profile of cortisol following a single dose administration of composition A

(6) FIG. 6 shows results from Example 18. The plasma concentration-time profile of cortisol following a single dose administration of composition B

(7) FIG. 7 shows results from Example 18. The plasma concentration-time profile of cortisol following a single dose administration of composition C

(8) FIG. 8 shows results from Example 19. The plasma concentration-time profile of cortisol following a single dose administration of film A. Non-mucoadhesive thin-layer film, 6 cm.sup.2, 10 mg hydrocortisone, buccal administration. Subject has the endogenous glucocorticoid secretion suppressed by synthetic glucocorticoids.

(9) FIG. 9 shows results from Example 19. The plasma concentration-time profile of cortisol following a single dose administration of film B. Non-mucoadhesive thin-layer film, 6 cm.sup.2, 11.2 mg hydrocortisone acetate, buccal administration. Subject has the endogenous glucocorticoid secretion suppressed by synthetic glucocorticoids.

(10) FIG. 10 shows results from Example 20. The plasma concentration-time profile of cortisol following a single dose administration of composition A. Muocadhesive thin-layer film, 10 mg hydrocortisone, buccal administration. Subject has the endogenous glucocorticoid secretion suppressed by synthetic glucocorticoids

(11) FIG. 11 shows results from Example 20. The plasma concentration-time profile of cortisol following a single dose administration of composition A. Mucoadhesive thin-layer film, 10 mg hydrocortisone, buccal administration. Subject has the endogenous glucocorticoid secretion suppressed by synthetic glucocorticoids

(12) FIG. 12 shows results from Example 21. The plasma concentration-time profile of cortisol following a single dose administration of-composition C. Mucoadhesive rapid-release tablet, 10 mg hydrocortisone, buccal administration. Subject has the endogenous glucocorticoid secretion suppressed by synthetic glucocorticoids

(13) FIG. 13 shows results from Example 22; dissolution curves of composition C from Example 21

(14) FIG. 14 shows results from Example 22; dissolution curves of composition A from Example 20

(15) FIG. 15 shows a target in vitro release of hydrocortisone (HC) from a combined IR/ER product. IR part: 30% of total dose; ER part: 70% of total dose; IR part: Releases >90% within 20 minutes, target: 100% as fast as possible (within 15 minutes); ER part: 90% with constant rate during 14-16 hours (In this example 15 hours). The remaining 10% will be released at a lower rate. The cumulative release is shown.

(16) FIG. 16 shows the same release as in FIG. 15 but here given as release rate (% released per hour)

(17) FIG. 17 shows a target in vitro release of hydrocortisone (HC) from a 15% IR and 85% ER combined IR/ER product; IR part: 15% of total dose with 50% released in 40 minutes. The rest is released within 75 minutes; ER part fast: 85% of total dose of which 90% is released during 10 hours (the rest at a lower rate); ER part slow: 85% of total dose of which 90% is released during 24 hours (the rest at a lower rate)

(18) FIG. 18 shows a target in vitro release of hydrocortisone (HC) from a combined IR/ER product. IR part: 50% of total dose; ER part: 50% of total dose; IR part: 50% of total dose with 50% released in 40 minutes. The rest is released within 75 minutes; ER part fast: 50% of total dose of which 90% is released during 10 hours (the rest at a lower rate); ER part slow: 50% of total dose of which 90% is released during 24 hours (the rest at a lower rate)

(19) FIGS. 19 and 20 are illustrations of different administration sites within the oral cavity

(20) The invention is further illustrated in the following non-limiting examples.

(21) Materials

(22) The materials used in the following examples were

(23) TABLE-US-00009 Chemical Trade name substance Manufacturer Acetone USP/NF Betamethasone USP/NF Calcium phosphate USP/NF Carboxymetylcellulose USP/NF Chitosan glutamate USP/NF Crospovidone USP/NF Ethylcellulose USP/NF Hydrocortisone Ph. Eur., Aventis, Qual. D Switzerland (by Apoteksbolaget) Hydrocortisone USP/NF acetate Hydrocortisone Ph. Eur Aventis, 21-hemisuccinate Switzerland (by sodium Apoteksbolaget) 2-OH-propyl-- cyclodextrin Hydroxypropylmethyl- USP/NF cellulose Lactose USP/NF Lactose anhydrous USP/NF Levomenthol USP/NF Magnesium stearate Magnesium Kissei, Japan stearate Menthol USP/NF Methocel E5 Hydroxypropyl- Dow Chemicals, methyl USA (by cellulose Colorcon) Methocel KV 100 USP/NF Dow Chemicals, LV USA (by Colorcon) Microcrystalline USP/NF FMC Corporation cellulose, Avicel PH-102 Paraffin powder USP/NF PEG 300 USP/NF PEG 6000 Polyethylene Svenska Hoechst glycol AB PEG 400 Polyethylene Fluka, glycol Switzerland Prednisolone USP/NF Polyox WSR 301 Polyethylene Dow Chemicals, oxide USA Silicon dioxide, USP/NF colloidal Sodium aluminium USP/NF silicate Sodium dihydrogen NaH.sub.2PO.sub.42 H.sub.2O phosphate Sodium stearyl USP/NF fumarate Sorbitol USP/NF Starch 1500, Pre-gelatinised Colorcon UK Colorcon UK starch Sugar USP/NF Sugar/starch seeds USP/NF Talc USP/NF Triethyl citrate USP/NF Xylitab 300 Xyrofin Kotka, Finland Xylisorb 300 (Danisco Sweeteners Ltd, UK Xylitol USP/NF Roquette, France
Methods

(24) The in vivo experiments reported herein were carried out on healthy volunteers. At 6 pm and 11 pm the day before administration of the test composition, the endogenous cortisol secretion was suppressed by oral administration of 2 mg of betamethasone.

(25) The test composition was administered to healthy volunteers. The volunteers were in fasted state and were not allowed to take any food until noon. In the case a tablet is administered, it is ingested together with 200 ml of water. The test composition is administered between 8 am and 10 am on the day following the suppression of endogenous glucocorticoid secretion.

EXAMPLES

Example 1

Porous Matrix Tablet Releasing the Glucocorticoid by Diffusion

(26) The following example relates to a porous matrix from which the glucocorticoid is released by diffusion. The matrix is coated with a film containing a readily water-soluble glucocorticoid for immediate release.

(27) TABLE-US-00010 Hydrocortisone 20 g Lactose 30 g Paraffin powder 20 g Sodium aluminium silicate 20 g
is dry mixed and granulated with a 5% ethanol solution of ethyl cellulose

(28) The wet mass is forced through a sieve, dried, milled and mixed with

(29) TABLE-US-00011 Calcium phosphate 40 g
and finally with

(30) TABLE-US-00012 Magnesium stearate 3 g

(31) The mixture is compressed into tablets containing 20 mg of hydrocortisone using 7 mm round concave punches. Approximate tablet weight 140 mg.

(32) The tablets are coated with a water suspension containing

(33) TABLE-US-00013 Hydrocortisone 21-hemisuccinate sodium 10% Hydroxypropyl methylcellulose 3% Talc 10%
until the coating on each tablet contains 6.7 mg of hydrocortisone 21-hemisuccinate sodium.

Example 2

Tablet Coated with a Water-Insoluble Film Containing a Pore-Forming Substance

(34) The following example relates to a tablet that is coated with a water-insoluble film containing a pore-forming substance. The tablet is further coated with a water-soluble film containing the part of the glucocorticoid for immediate release.

(35) TABLE-US-00014 Hydrocortisone 21-hemisuccinate sodium 20 g Calcium phosphate 75 g Talc 5 g Magnesium stearate 2 g
are dry mixed and compressed into tablets containing 20.1 mg of hydrocortisone 21-hemisuccinate sodium using 6 mm round concave punches with bevelled edges. Approximate tablet weight 103 mg.

(36) The tablets are coated with an acetone suspension of

(37) TABLE-US-00015 Ethyl cellulose 5% Sugar micronized to a particle size < 10 m 10%
until each tablet carries a coating of about 40 mg.

(38) The tablets are further coated with a water suspension containing

(39) TABLE-US-00016 Hydrocortisone 21-hemisuccinate sodium 10% Hydroxypropyl methylcellulose, 6 cps 3% Talc 10%
until the outer coating on each tablet contains 6.7 mg of hydrocortisone 21-hemisuccinate sodium.

Example 3

Hydrophilic Matrix Tablet

(40) This example relates to a hydrophilic gel matrix tablet that is dry coated with a coating containing the part of the glucocorticoid for immediate release.

(41) TABLE-US-00017 Hydrocortisone 20 g Sodium aluminium silicate 15 g Hydroxypropyl methylcellulose, 60 cps 80 g
are mixed and granulated with ethanol. The wet mass is forced through a sieve, dried and milled. To the dry mixture is added

(42) TABLE-US-00018 Talc 5 g Magnesium stearate 2 g

(43) After mixing for about 2 minutes the mixture is compressed into extended release tablets using 7 mm round flat punches. Each tablet contains 20 mg of hydrocortisone and has an approximate tablet weight of 117 mg.

(44) TABLE-US-00019 Hydrocortisone 10 g Lactose 40 g Hydroxypropyl methylcellulose, 6 cps 5 g
are dry mixed and then granulated with water. The wet mass is forced through a sieve, dried and milled. To the dry mass is added

(45) TABLE-US-00020 Polyvinylpyrollidone cross-linked 5 g

(46) After mixing is added

(47) TABLE-US-00021 Magnesium stearate 1 g
and mixing is continued during another 2 minutes.

(48) Dry coated tablets are made by compressing about 61 mg of the tablet mass above around each extended release tablet using a Manesty DryCota tableting machine equipped with 9 mm round concave punches. The press-coated layer contains 10 mg of hydrocortisone.

Example 4

Capsules Containing a Mixture of Pellets for Immediate (IR Pellets) and Extended Release (ER Pellets)

(49) ER Pellets

(50) TABLE-US-00022 Sugar/starch seeds, diameter 0.25-0.35 mm 1 kg
are first coated in a fluidised bed equipped with a Wurster column with an ethanol/acetone 40/60 solution of

(51) TABLE-US-00023 Ethyl cellulose 10 cps .sup.5% Triethyl citrate 0.4%
to a coating thickness of about 3 m
and then further coated with an ethanol/acetone 40/60 solution of

(52) TABLE-US-00024 Hydrocortisone 5% Hydroxypropyl methylcellulose 6 cps 1%
to a weight gain of approximately 25%.

(53) Using the same equipment the pellets are further coated with an ethanol/acetone 40/60 solution of

(54) TABLE-US-00025 Ethyl cellulose 10 cps .sup.5% Hydroxypropyl methylcellulose 6 cps 1.5% Triethyl citrate 0.3%
to a coating thickness of 20 m.
IR Pellets

(55) TABLE-US-00026 Sugar/starch seeds, diameter 0.25-0.35 mm 1 kg
are coated in a fluidised bed equipped with a Wurster column with a water suspension containing

(56) TABLE-US-00027 Hydrocortisone 21-hemisuccinate sodium 10% Hydroxypropyl methylcellulose, 6 cps 3% Talc 10%
to a weight gain of approximately 75%.

(57) An amount of ER pellets containing 20 mg of hydrocortisone (approximately 140 mg) and an amount of IR pellets containing 13.4 mg of hydrocortisone 21-hemisuccinate sodium (approximately 70 mg) are filled into hard gelatine capsules size No 2 in a two-station capsule-filling machine.

Example 5

Two-Layered Tablets

(58) This example relates to a two-layered tablet comprising a hydrophilic gel matrix tablet for extended release on which a further layer is compressed containing the part of the glucocorticoid for immediate release.

(59) TABLE-US-00028 Hydrocortisone 20 g Sodium aluminium silicate 15 g Hydroxypropyl methylcellulose, 60 cps 80 g
is granulated with ethanol. The wet mass is forced through a sieve, dried and milled.

(60) To the dry mixture is added

(61) TABLE-US-00029 Talc 5 g Magnesium stearate 2 g

(62) After mixing for about 2 minutes the mixture is at a low compression force compressed into about 117 mg tablets using 8 mm round flat punches in the first station of a two-station tabletting machine. Each tablet contains 20 mg of hydrocortisone.

(63) TABLE-US-00030 Hydrocortisone 10 g Lactose 40 g Hydroxypropyl methylcellulose, 6 cps 5 g
are dry mixed and then granulated with water. The wet mass is forced through a sieve, dried and milled.

(64) To the dry mass is added

(65) TABLE-US-00031 Polyvinylpyrollidone cross-linked 5 g

(66) After mixing is added

(67) TABLE-US-00032 Magnesium stearate 1 g
and mixing is continued during another 2 minutes.

(68) Two-layer tablets are made by filling about 61 mg (containing 10 mg of hydrocortisone) of the tablet mass on top of the loosely compressed tablets above in the second station of the tabletting machine.

Example 6

(69) ER Tablets

(70) TABLE-US-00033 Mg per tablet Hydrocortisone 20 Methocel KV 100 LV 64 Microcrystalline cellulose, Avicel PH-102 98 Starch 1500, Colorcon UK 16 Silicon dioxide, colloidal 1 Magnesium stearate 1

(71) All materials, except for magnesium stearate, were dry mixed until homogeneous. Magnesium stearate was added and mixing was continued during another two minutes. The powder blend was compressed into 200 mg tablets using 8 mm round concave punches. The tablets had a mean tablet height of 4.25 mm and a mean crushing strength of 10.8 kp. The average content of hydrocortisone was 19.3 mg per tablet.

(72) The tablets were analysed with respect to dissolution rate using USP Dissolution Apparatus No 2, paddle, with 500 ml simulated intestinal fluid without enzymes and a stirring rate of 50 rpm. Samples were withdrawn at different times and analysed for hydrocortisone by HPLC. The median results for three individually analysed tablets were:

(73) TABLE-US-00034 Time 1 h 3 h 5 h 7 h 9 h 11 h 13 h 15 h % dissolved 7 24 41 58 70 83 90 95

(74) The extended release tablets were tested in human volunteers. FIG. 1 shows the results obtained.

(75) In a fluidised bed equipped with a Wurster column the ER tablets are coated with a water suspension containing

(76) TABLE-US-00035 Hydrocortisone 2% Hydroxypropyl methylcellulose 0.7%.sup. Talc 2%
until the coating on each tablet contains 7 mg of hydrocortisone.

(77) The coating is rapidly dissolving and dissolution is complete within 15 minutes.

(78) The cumulative dissolution of hydrocortisone of the coated tablets is shown in FIG. 2.

Example 7

Kit Containing an Immediate Release (IR) Tablet and an Extended Release (ER) Tablet

(79) IR tablets for oral or sublingual use:

(80) TABLE-US-00036 Mg per tablet Betamethasone 0.4 Xylitab300.sup.a 40 Lactose anhydrous USP/NF 5 Microcrystalline cellulose USP/NF 10 Crospovidone USP/NF 4 Sodium stearyl fumarate 1 Water qs .sup.aDirect compression xylitol from Danisco Sweeteners Ltd UK

(81) Dry mix lactose and microcrystalline cellulose. Dissolve betamethasone in a small amount of water and disperse the solution over the powder blend. Mix and dry. Add Xylitab and crospovidone and dry mix until the blend is homogeneous. Add sodium stearyl fumarate and continue blending for another 2 minutes. Compress the blend to tablets in a tablet press using 6 mm round concave punches.

(82) ER Tablets:

(83) TABLE-US-00037 Mg per tablet Betamethasone 0.8 Methocel K100 Premium LV CR.sup.b 65 Microcrystalline cellulose USP/NF 70 Colloidal silicon dioxide 1 Magnesium stearate 1 .sup.bDow Chemical Company

(84) Blend all materials, except for magnesium stearate, until homogeneous in a suitable mixer. Then add magnesium stearate and blend for another 2 minutes. Compress to tablets in a tablet press equipped with 7.5 mm round concave punches.

(85) Package one IR tablet and one ER tablet in a suitably designed package to obtain a kit.

Example 8

Kit Containing an Immediate Release (IR) Film and an Extended Release (ER) Tablet

(86) Thin films for administration to the oral cavity:

(87) TABLE-US-00038 % by weight Prednisolone 0.75 PEG 400 USP/NF 2 Methocel E5, Dow Chemical 4 Xylitol, Roquette France 1 Water up to 100

(88) Methocel was added to approximately 90% of the total amount of distilled water and stirred with a magnetic stirrer until Methocel was completely dissolved. PEG 400 was added under continued stirring, followed by xylitol and prednisolone. Water was added to final weight and stirring was continued during four hours.

(89) 330 l of the solution was pipetted into 16 mm diameter flat-bottomed PVC blisters. The solutions were allowed to dry at room temperature over night and the blister packs were sealed with heat-seal lacquered aluminium foil.

(90) ER Tablets:

(91) TABLE-US-00039 Mg per tablet Prednisolone 1.5 Methocel K100 Premium LV CR.sup.b 65 Microcrystalline cellulose USP/NF 70 Colloidal silicon dioxide 1 Magnesium stearate 1 .sup.bDow Chemical Company

(92) Blend all materials, except for magnesium stearate, until homogeneous in a suitable mixer. Then add magnesium stearate and blend for another 2 minutes. Compress to tablets in a tablet press equipped with 7.5 mm round concave punches.

(93) Package one IR film blister and one ER tablet to obtain a suitably designed kit.

Example 9

Kit Containing an Immediate Release (IR) Oral Solution and an Extended Release (ER) Tablet

(94) Oral Solution:

(95) TABLE-US-00040 Prednisolone acetate 0.9 mg Sorbitol 60 mg Menthol 1.2 mg Sterile water 5 ml

(96) Make a solution and fill into a moisture tight aluminium foliated sachet.

(97) Package one sachet and one ER tablet to obtain a suitably designed kit.

Example 10

Kit Containing an Immediate Release (IR) Sublingual Spray and an Extended Release (ER) Tablet

(98) Sublingual Spray of Hydrocortisone:

(99) TABLE-US-00041 mg/ml Hydrocortisone acetate 10 Carboxymetylcellulose 0.8 (0.08%) 2-OH-propyl--cyclodextrin 40 PEG 300 5 Menthol 0.3 Sorbitol 12 Levomenthol 2.0 NaH.sub.2PO.sub.42H.sub.2O 2 Water qs

(100) Dissolve hydrocortisone acetate in a small amount of water. Mix with 2-OH-propyl--cyclodextrin, let stand for 1 hour. Add carboxymethylcellulose and mix. Add PEG 300, menthol, sorbitol, levomenthol and NaH.sub.2PO.sub.4.Math.2 H.sub.2O. Add water up to final volume. Dispense into a spray package that delivers 0.58 ml per dose (5 mg of hydrocortisone).

(101) Hydrocortisone ER Tablets

(102) TABLE-US-00042 Mg per tablet Hydrocortisone 10 Methocel KV 100 LV 64 Microcrystalline cellulose, Avicel PH-102 98 Starch 1500, Colorcon UK 16 Silicon dioxide, colloidal 1 Magnesium stearate 1

(103) Dry mix all materials, except for magnesium stearate, until homogeneous. Add magnesium stearate and continue mixing another two minutes. Compress the powder blend into 200 mg tablets using 8 mm round concave punches.

(104) Dispense the sublingual spray and ER tablets into suitably designed kit(s).

Example 11

Kit Containing an Immediate Release Film and an Extended Release Tablet

(105) A kit is provided containing i) an immediate release film containing 10 mg hydrocortisone and prepared as described in example 20 composition A and ii) an extended release tablet containing 20 mg hydrocortisone and prepared according to Example 6. The component i) is administered buccally and the component ii), i.e. the tablet is ingested together with 200 ml of water. The two components are taken simultaneously. The results are shown in FIG. 3.

Example 12

Kit Containing an Oral Solution of Hydrocortisone for Immediate Release and an Extended Release Tablet

(106) An oral solution is prepared by dissolving 10 mg of hydrocortisone in 200 ml of water and the extended release tablet corresponds to that of Example 6. The two compositions are given to human volunteers simultaneously and the results are shown in FIG. 4.

(107) In the following are described examples of immediate release compositions. Each of the exemplified compositions can be used as an immediate release component in a kit according to the invention. The extended release component may be any suitable glucocorticoid-containing composition releasing the glucocorticoid in an extended manner as defined herein.

Example 13

Betamethasone IR Tablet for Peroral or Buccal Administration

(108) TABLE-US-00043 Mg per tablet Betamethasone 0.4 Xylitab300.sup.a) 45 Microcrystalline cellulose NF 10 Crospovidone NF 4 Water qs Sodium stearyl fumarate NF 1 .sup.a)Direct compression xylitol from Danisco Sweeteners Ltd, UK

(109) Dissolve betamethasone in a small amount of water.

(110) Disperse the solution over the microcrystalline cellulose. Mix and dry.

(111) Add Xylitab and crospovidone and dry mix in a suitable mixer until a homogeneous blend is achieved.

(112) Then add sodium stearyl fumarate and continue mixing another two minutes. Compress the powder blend in a suitable tablet press using 6 mm round concave punches.

Example 14

Sublingual Spray of Betamethasone

(113) TABLE-US-00044 mg/ml Betamethasone 0.4 Carboxymetylcellulose 0.8 (0.08%) PEG 300 5 Menthol 0.3 Sorbitol 12 Levomenthol 2.0 NaH.sub.2PO.sub.4*2H.sub.2O 2 Water qs

(114) Dissolve betamethasone in a small amount of water. Add carboxymetylcellulose and mix. Add PEG 300, menthol, sorbitol, levomenthol and NaH.sub.2PO.sub.4*2 H.sub.2O. Add water up to final volume.

Example 15

Sublingual Spray of Betamethasone

(115) TABLE-US-00045 mg/ml Betamethasone 0.4 Chitosan glutamate 10 Menthol 0.1 Levomenthol 1.5 NaH.sub.2PO.sub.4*2H.sub.2O 2 Water qs

(116) Dissolve betamethasone in a small amount of water. Add chitosan glutamate and mix. Filter through 0.2 m membrane filter. Add menthol, levomenthol and NaH.sub.2PO.sub.4*2 H.sub.2O. Add water up to final volume.

Example 16

Sublingual Spray of Hydrocortisone

(117) TABLE-US-00046 Hydrocortisone acetate 10 Carboxymetylcellulose 0.8 (0.08%) 2-OH-propyl--cyclodextrin 40 PEG 300 5 Menthol 0.3 Sorbitol 12 Levomenthol 2.0 NaH.sub.2PO.sub.4*2H.sub.2O 2 Water qs

(118) Dissolve hydrocortisone in a small amount of water. Mix with 2-OH-propyl--cyclodextrin, let stand for 1 hour. Add carboxymethylcellulose and mix. Add PEG 300, menthol, sorbitol, levomenthol and NaH.sub.2PO.sub.4*2 H.sub.2O. Add water up to final volume.

Example 17

Sublingual Spray of Hydrocortisone

(119) TABLE-US-00047 mg/ml Hydrocortisone acetate 10 Chitosan glutamate 10 2-OH-propyl--cyclodextrin 40 Menthol 0.1 Levomenthol 1.5 NaH.sub.2PO.sub.4*2H.sub.2O 2 Water qs

(120) Dissolve hydrocortisone in a small amount of water. Mix with 2OH-propyl--cyclodextrin, let stand for 1 hour. Add chitosan glutamate and mix. Filter through 0.2 m membrane filter. Add menthol, levomenthol and NaH.sub.2PO.sub.4*2 H.sub.2O. Add water up to final volume.

Example 18

Thin-layer Film of Hydrocortisone

(121) Composition A:

(122) TABLE-US-00048 % w/w Hydrocortisone 3% Na-alginate PH157 2% Water 95%
Composition B:

(123) TABLE-US-00049 Hydrocortisone acetate 3.4% Na-alginate PH157 2% Water 94.6%
Composition C:

(124) TABLE-US-00050 Hydrocortisone 3% Metolose 60SH-50 2% Water 95%

(125) The films were made as described in the following: 1. Amount polymer, glucocorticoid and H.sub.2O were weighed. 2. The glucocorticoid was added to the water during stirring. 3. The formulation was kept on stirring until a suspension was obtained. 4. The polymer was added to the suspension. 5. The formulation was kept on stirring until a uniform gel was obtained (minimum 2 h). 6. 0.5 g gel was weighed in empty blisters and placed in a heating cupboard (Drying: 25 C. for 22 h).

(126) Table. In vitro dissolution (rotating basket 100 rpm, phosphate buffer pH=7.0, one unit per 500 ml medium) after 1, 3, 5, 10 and 15 min as a percentage of 10 mg hydrocortisone. Units with 10 mg hydrocortisone in polymers of sodium alginate (Na-alg), hypromeilose (HPMC) and approx. 7 mg/unit. Two units were tested with Na-alg and HPMC. The mean value is tabulated. The results in the following table reflect the rank order regarding viscosity, i.e. HPMC has the lowest viscosity and Na-aig the highest.

(127) TABLE-US-00051 1 min, 3 min, 5 min, 10 min, 15 min, Composition Polymer % % % % % A Na-alg 15 25 38 65 84 B Na-alg 15 25 38 65 84 C HPMC 18 48 67 88 92

(128) In vivo plasma profiles in humans, N=1 per composition

(129) Dexamethasone suppression test, fasting state, otherwise as described in the paragraph denoted Method.

(130) The results show (FIGS. 5-7) that the use of hydrocortisone acetate does not seem to be suitable for an immediate release composition. This was further investigated in the following example.

Example 19

Non-Mucoadhesive Immediate Release Films

(131) Two films were prepared essentially similar to Example 20composition A. Film A contains 10 mg of hydrocortisone and film B contains 11.2 mg of hydrocortisone acetate. The results from in vivo testing after buccal administration are shown in FIGS. 8 and 9. The results show that even if the films are not bioadhesive, a fast onset of the absorption into the systemic circulation after single dose administration of Film A is obtained. In contrast, the results obtained with the film containing hydrocortisone acetate indicate that this compound does not seem to be suitable when a fast onset of the absorption into the systemic circulation of the glucocorticoid is required.

Example 20

Thin-Layer Films for Immediate Release or Extended Release

(132) Batches of glucocorticoid films were prepared from the following compositions A and B:

(133) TABLE-US-00052 Rapid-release composition A: Component % w/w PEG 400 2.0 Hydrocortisone 3.0 Methocel E5 4.0 Xylitol 1.0 Water 90

(134) TABLE-US-00053 Slower release composition B: Component w/w % PEG 400 1.3 Hydrocortisone 3.0 Methocel E5 5.7 Water 90

(135) To distilled water (18 ml) in 50 ml round-bottomed glass flask provided with a magnetic stirred was added Methocel E5. After the Methocel had dissolved completely PEG 400 was added under continued stirring, followed by xylitol (Composition A only) and hydrocortisone. Stirring was continued for 4 h.

(136) Into flat-bottomed PVC-blisters (Inpack AB, Lund, Sweden) 16 mm in diameter was pipetted (Finnpipette; automatic) 330 l of solution A or B into each blister trough. The solutions were allowed to dry at Mom temperature over night. The next day 10 films were removed for dose analysis. Each film was dissolved in 100 ml of water/ethanol (95%) 9:1 (w/w). The solutions were analysed by UV spectroscopy at 242 nm. Mean contents of 10.19 mg and 9.83 mg hydrocortisone per blister (SD 0.29 and 0.14, respectively) were found for Compositions A and B, respectively.

(137) The hydrocortisone compositions were tested in two human subjects after labial administration. The subjects had their endogenous glucocorticoid secretion suppressed by synthetic glucocorticoids. The plasma concentration of cortisol was monitored during 360 min after the labial administration, and the serum concentration time profiles from these two different subjects are shown in FIGS. 10 and 11.

(138) It is clearly seen that the rate and extent of mucosal uptake of hydrocortisone is high and the appearance of cortisol in serum is rapid, as the first measured plasma concentration was attained already at 10-15 min.

(139) These serum pharmacokinetic data illustrate that a formulation of the invention for oral mucosa administration results in a high rate and extent of mucosal absorption of the active drug, even though a small volume of fluid is available for dissolution at the site of administration and absorption in this route of drug delivery.

Example 21

Glucocorticoid Tablets for Immediate or Extended Release

(140) Glucocorticoid tablets were manufactured by direct compression of the dry-mixed powderous components to the following compositions C and D:

(141) TABLE-US-00054 Component Per Batch Rapid-release composition C: PEG 6000 8.7 g Hydrocortisone 2.5 g Xylitab 300 8.7 g Mg stearate 0.16 g Slow-release composition D: PEG 6000 6.94 g Hydrocortisone 2.5 g Xylisorb 6.94 g Polyox WSR 301 3.46 g Mg stearate 0.16 g
Batch Size 100 Tablets

(142) The powderous components were sieved (mesh size 0.7 mm) and dry-mixed by shaking by hand in a small tin can for five min. The homogeneity of the mixture was analyzed by the same method as used for analysis of the tablets. Tabletting was carried out with a DIAF tabletting machine using a flat circular punch 7 mm in diameter (with a dividing score). The hydrocortisone dose in 10 tablets was assessed by the same method as used for the films. Mean contents of 9.53 mg and 9.72 mg hydrocortisone per tablet (SD 0.15 and 0.14, respectively) were found for compositions C and D, respectively.

(143) Tablet thickness (10 tablets): 1.72-1.78 mm (C); 1.79-1.84 mm (D).

(144) Friability (20 tablets): 0.6% (C); 0.4% (D).

(145) Tablet hardness (10 tablets): 23.7 N(C); 22.9 N (D).

(146) The compositions were tested after oral administration to two human subjects (FIG. 12).

(147) The rate of absorption of the active substance into the systemic circulation from the solid dosage forms of Example 21 was somewhat slower than that of compositions from Example 20, which means that it is possible to adjust the absorption rate of hydrocortisone into the systemic circulation by introducing changes in the composition and function of the labial pharmaceutical formulation.

Example 22

In Vitro Dissolution Profile

(148) The in vitro dissolution profiles of hydrocortisone from drug formulations according to Example 20 and 21 were followed over time in a standardized controlled in vitro environment. A United States Pharmacopoeia dissolution apparatus II (paddle) coupled to automatic sampling devices and software was used for acquiring release profiles of the drug formulations in a neutral pH environment. The dissolution profile was acquired at 37 C., 50 rpm of the paddles, in a total of 300 ml of water. Sampling was performed at 0, 1, 3, 5, 7, 10 and 15 minutes following the insertion of the pharmaceutical composition in the example in the dissolution medium.

(149) The dissolution profile from each formulation was monitored in two experiments up to 360 min after administration, and the corresponding dissolution time profiles are shown in FIGS. 13 and 14, respectively. The release rate is given as the percent of dose over time.

(150) The release rate from the solid dosage forms of Example 21 was somewhat slower (FIG. 14). This means that it is possible to adjust the release rate of hydrocortisone by introducing changes in the composition and function of the oronasopharyngeal pharmaceutical preparation.