SEALING FLUID FOR SEALING CAPSULES

Abstract

The present invention discloses a sealing fluid comprising an organic acid, an alcohol and optionally water, the organic acid is lactic acid or acetic acid, the alcohol is isopropanol or ethanol, the sealing fluid is a liquid composition for sealing telescopically joined hard capsules with coaxial partly overlapping body parts.

Claims

1. A sealing fluid for sealing hard capsules, comprising: an organic acid, wherein the organic acid is lactic acid or acetic acid; and an alcohol, wherein the alcohol is isopropanol or ethanol, wherein an amount of the organic acid is at least 32.5 wt % and an amount of the alcohol is at least 17.5 wt %, the wt % being based on the weight of the sealing fluid; the sealing fluid does not contain hydroxypropyl methylcellulose (HPMC); and the sealing fluid has a viscosity of 100 mPa*s or below, with the viscosity measured at 22 C. with a rotational viscometer with a cylindrical spindle.

2. The sealing fluid according to claim 1, wherein the sealing fluid consists of the organic acid and the alcohol.

3. The sealing fluid according to claim 2, wherein the organic acid is acetic acid.

4. The sealing fluid according to claim 2, wherein the alcohol is isopropanol.

5. The sealing fluid according to claim 3, wherein the amount of the acetic acid is from 47.5 wt % to 80 wt % and the amount of the alcohol is from 20 wt % to 52.5 wt %, the wt % being based on the weight of the sealing fluid.

6. The sealing fluid according to claim 1, wherein: the sealing fluid further comprises water; and the sum of the amounts of the organic acid, the alcohol, and water are at least 97.5 wt %, with the wt % being based on the weight of the sealing fluid.

7. The sealing fluid according to claim 6, wherein the amount of water in the sealing fluid is at least 17.5 wt %, with the wt % being based on the weight of the sealing fluid.

8. The sealing fluid according to claim 6, wherein: the organic acid is acetic acid; the amount of the acetic acid is from 40 wt % to 60 wt %; and the amount of the alcohol is from 20 wt % to 40 wt %, the wt % being based on the weight of the sealing fluid.

9. The sealing fluid according to claim 8, wherein the alcohol is isopropanol.

10. The sealing fluid according to claim 6, wherein: the organic acid is lactic acid; the amount of the lactic acid is from 32.5 wt % to 62.5 wt %; and the amount of the alcohol is from 17.5 wt % to 47.5 wt %, the wt % being based on the weight of the sealing fluid.

11. The sealing fluid according to claim 10, wherein: the alcohol is ethanol; and the amount of the ethanol is from 25 wt % to 42.5 wt %, the wt % being based on the weight of the sealing fluid.

12. The sealing fluid according to claim 10, wherein: the alcohol is isopropanol; the amount of the lactic acid is from 37.5 wt % to 55 wt %; and the amount of the isopropanol is from 17.5 wt % to 42.5 wt %, the wt % being based on the weight of the sealing fluid.

13. The sealing fluid according to claim 12, wherein: the amount of the lactic acid is from 37.5 wt % to 45 wt %; the amount of the isopropanol is from 35 wt % to 42.5 wt %, the wt % being based on the weight of the sealing fluid.

14. The sealing fluid according to claim 6, wherein the sealing fluid consists of the organic acid, the alcohol, and water.

15. The sealing fluid according to claim 14, wherein the organic acid is lactic acid.

16. The sealing fluid according to claim 14, wherein the alcohol is isopropanol.

17. The sealing fluid according to claim 14, wherein the amount of the organic acid is 40 wt %; and the amount of the alcohol is 40 wt %, the wt % being based on the weight of the sealing fluid.

18. A method of preparation of the sealing fluid of claim 1, comprising: mixing the organic acid, the alcohol, and any water.

19. A method for sealing a hard capsule, wherein a capsule shell of the hard capsule consists of a cap and a body with the body being telescopically inserted into the cap providing a slit between the overlapping parts of the cap and the body, the method comprising: sealing the hard capsule by applying the sealing fluid of claim 1 onto said slit.

20. A sealed hard capsule obtainable by the method of claim 19.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0017] In one embodiment, SEALFLU does not contain any polymer which is conventionally used in the preparation of capsules, such as gelatin, pullulan, starch, modified starch, or cellulose derivatives such as HPMC.

[0018] More preferably, SEALFLU does not contain any polymer.

[0019] More preferably, SEALFLU does not contain any gelation agent.

[0020] More preferably, SEALFLU does not contain any substance that increases by its addition the viscosity of SEALFLU, in particular not over 100 mPa*s, with the viscosity measured at 22 C. with a rotational viscometer with a cylindrical spindle.

[0021] Preferably, the amount of ALC is at least 20 wt %; more preferably at least 25 wt %, even more preferably at least 30 wt %, especially at least 35 wt %, the wt % being based on the weight of SEALFLU.

[0022] Preferably, the amount of ALC is not more than 55 wt %, more preferably not more 50 wt %, even more preferably not more 45 wt %, the wt % being based on the weight of SEALFLU.

[0023] Any of the lower limits may be combined with any of the upper limits of the possible amounts of ALC.

[0024] Preferably, the amount of ORGACID is at least 35 wt %, the wt % being based on the weight of SEALFLU.

[0025] Preferably, the amount of ORGACID is not more than 75 wt %, more preferably at least 70 wt %, even more preferably not more 65 wt %, especially not more than 60 wt %, more especially not more than 55 wt %, even more especially not more than 50 wt %, in particular not more than 45 wt %, the wt % being based on the weight of SEALFLU.

[0026] Any of the lower limits may be combined with any of the upper limits of the possible amounts of ORGACID.

[0027] Any of the lower or upper limits of the possible amounts of ALC may be combined with any of the lower or upper limits of the possible amounts ORGACID.

[0028] In one embodiment, SEALFLU consists of ORGACID and ALC; [0029] preferably ORGACID is acetic acid; or [0030] preferably ALC is isopropanol; [0031] more preferably in this case ORGACID is acetic acid and ALC is isopropanol.

[0032] In one embodiment, SEALFLU consists of ORGACID and ALC; ORGACID is acetic acid; [0033] the amount of acetic acid is from 47.5 to 80 wt % and the amount of ALC is from 20 to 52.5 wt %, [0034] preferably the amount of acetic acid is from 47.5 to 75 wt % and the amount of ALC is from 25 to 52.5 wt %; [0035] the wt % being based on the weight of SEALFLU; [0036] preferably, ALC is isopropanol.

[0037] In one embodiment, SEALFLU comprises besides ORGACID and ALC also water; [0038] the sum of the amounts of ORGACID, ALC and water are at least 97.5 wt %, preferably 98 wt %, more preferably at least 99 wt %, even more preferably it is 100 wt %, that is SEALFLU consists of ORGACID, ALC and water, with the wt % being based on the weight of SEALFLU.

[0039] Preferably, when SEALFLU comprises besides ORGACID and ALC also water, then the amount of water in SEALFLU is at least 17.5 wt %, with the wt % being based on the weight of SEALFLU; preferably in this case ORGACID is lactic acid.

[0040] In one embodiment, SEALFLU comprises besides ORGACID and ALC also water; ORGACID is acetic acid; [0041] the amount of acetic acid is from 40 to 60 wt %; [0042] the amount of ALC is from 20 to 40 wt %; [0043] the sum of the amounts of ORGACID, ALC and water are at least 97.5 wt %, preferably 98 wt %, more preferably at least 99 wt %, even more preferably the sum of the amounts of ORGACID, ALC and water is 100 wt %, that is SEALFLU consists of ORGACID, ALC and water; [0044] the wt % being based on the weight of SEALFLU; [0045] preferably ALC is isopropanol.

[0046] In one embodiment, SEALFLU comprises besides ORGACID and ALC also water; ORGACID is acetic acid; [0047] the amount of acetic acid is from 45 to 55 wt %; [0048] the amount of ALC is from 25 to 35 wt %; [0049] the sum of the amounts of ORGACID, ALC and water are at least 97.5 wt %, preferably 98 wt %, more preferably at least 99 wt %, even more preferably the sum of the amounts of ORGACID, ALC and water is 100 wt %, that is SEALFLU consists of ORGACID, ALC and water; [0050] the wt % being based on the weight of SEALFLU; [0051] preferably ALC is isopropanol.

[0052] In one embodiment, SEALFLU comprises besides ORGACID and ALC also water; [0053] ORGACID is lactic acid; [0054] the amount of lactic acid is from 32.5 to 62.5 wt %; [0055] the amount of ALC is from 17.5 to 47.5 wt %; [0056] the sum of the amounts of ORGACID, ALC and water are at least 97.5 wt %, preferably 98 wt %, more preferably at least 99 wt %, even more preferably the sum of the amounts of ORGACID, ALC and water is 100 wt %, that is SEALFLU consists of ORGACID, ALC and water;
preferably ALC is ethanol and the amount of ethanol is from 25 to 42.5 wt %, more preferably from 27.5 to 42.5 wt %;
the wt % being based on the weight of SEALFLU.

[0057] In one embodiment, SEALFLU comprises besides ORGACID and ALC also water; ORGACID is lactic acid; [0058] the amount of lactic acid is from 32.5 to 55 wt %; [0059] the amount of ALC is from 17.5 to 42.5 wt %; [0060] the sum of the amounts of ORGACID, ALC and water are at least 97.5 wt %, preferably 98 wt %, more preferably at least 99 wt %, even more preferably the sum of the amounts of ORGACID, ALC and water is 100 wt %, that is SEALFLU consists of ORGACID, ALC and water; [0061] preferably, ALC is ethanol and the amount of ethanol is from 25 to 42.5 wt %, more [0062] preferably from 27.5 to 42.5 wt %; [0063] the wt % being based on the weight of SEALFLU.

[0064] In one embodiment, SEALFLU comprises besides ORGACID and ALC also water; [0065] ORGACID is lactic acid and ALC is isopropanol; [0066] the amount of lactic acid is from 37.5 to 55 wt %; [0067] the amount of isopropanol is from 17.5 to 42.5 wt %; [0068] the sum of the amounts of ORGACID, ALC and water are at least 97.5 wt %, preferably 98 wt %, more preferably at least 99 wt %, even more preferably the sum of the amounts of ORGACID, ALC and water is 100 wt %, that is SEALFLU consists of ORGACID, ALC and water; [0069] the wt % being based on the weight of SEALFLU.

[0070] In one embodiment, SEALFLU comprises besides ORGACID and ALC also water; [0071] ORGACID is lactic acid and ALC is isopropanol; [0072] the amount of lactic acid is from 37.5 to 45 wt %; [0073] the amount of isopropanol is from 35 to 42.5 wt %, [0074] the sum of the amounts of ORGACID, ALC and water are at least 97.5 wt %, preferably 98 wt %, more preferably at least 99 wt %, even more preferably the sum of the amounts of ORGACID, ALC and water is 100 wt %, that is SEALFLU consists of ORGACID, ALC and water; [0075] the wt % being based on the weight of SEALFLU.

[0076] In one embodiment, SEALFLU consists of ORGACID and ALC and water;

preferably, ORGACID is lactic acid; or
preferably, ALC is isopropanol;
more preferably, ORGACID is lactic acid and ALC is isopropanol.

[0077] In one embodiment, SEALFLU consists of ORGACID and ALC and water; [0078] the amount of ORGACID is 40 wt %, [0079] the amount of ALC is 40 wt %,
the wt % being based on the weight of SEALFLU;
preferably, ORGACID is lactic acid; or
preferably, ALC is isopropanol;
more preferably, ORGACID is lactic acid and ALC is isopropanol.

[0080] Any water may be demineralized water.

[0081] SEALFLU may have a viscosity of 100 mPa*s or below, preferably of 75 mPa*s or below, more preferably of 60 mPa*s or below, even more preferably of 50 mPa*s or below, especially of 45 mPa*s or below, more especially of 40 mPa*s or below, with the viscosity measured at 22 C. with a rotational viscometer with a cylindrical spindle.

[0082] In one embodiment, SEALFLU has a viscosity which is equal or lower than the viscosity of pure lactic acid, with the viscosity measured at 22 C. with a rotational viscometer with a cylindrical spindle.

[0083] Further subject of the invention is a method of preparation of SEALFLU, wherein ORGACID and ALC and any water are mixed;

with SEALFLU, ORGACID and ALC as defined herein, also with all their embodiments.

[0084] The mixing of ORGACID, ALC and water can be done in any order.

[0085] Further subject of the invention is a method, METHSEAL, for sealing a hard capsule, the capsule shell of the capsule consists of a cap and a body with the body being telescopically inserted into the cap providing a slit between the overlapping parts of the cap and the body; wherein the sealing is done by applying SEALFLU onto said slit;

with SEALFLU as defined herein, also with all its embodiments.

[0086] The capsule is filled and closed before the sealing. When closing the capsule cap and the body are telescopically joined. This joining can be done for example by inserting the body into the cap, that is the body slides into the cap, or the other way around. The cap and the body partly overlap in the closed capsule. Thereby a slit is formed between the overlapping parts of the cap and the body. When sealing the capsule the sealing fluid is applied onto the slit, that is onto the beginning of this slit which is approachable from the outside of the capsule. The beginning of the slit is located between the rim of the cap and the surface of the body.

[0087] SEALFLU may be uniformly around the capsule, thereby also onto the slit, or it may be applied onto the slit only. SEALFLU may be applied onto the slit over the whole length of the slit or only to a part or to parts of the length of the slit. Preferably it is applied over the whole length of the slit.

[0088] SEALFLU may be applied by spraying onto the slit or onto the capsule and thereby also onto the slit.

[0089] SEALFLU may have ambient temperature or a temperature below ambient temperature when it is applied onto the capsule, that is onto the slit.

[0090] After the application of SEALFLU onto the slit the capsule may be dried. This drying may for example be done to remove any excess of SEALFLU. It may also be done to ensure that the surfaces of the overlapping parts of the cap and the body, that is the surfaces of the cap and the body that form the slit, securely bond to each other.

[0091] Further subject of the invention is a sealed capsule obtainable by the method METHSEAL; with METHSEAL as defined herein, also with all its embodiments.

[0092] Capsules suitable for the method for sealing a hard capsule of the present invention may have a shell made out of known film forming polymers such as gelatin, HPMC, pullulan or starch. The capsule shell may comprise further components such as a gelling system, a typical gelling system is gellan. In one embodiment the method for sealing a hard capsule of the present invention is a method for sealing hard capsules wherein the film forming polymer of the capsule shell is gelatin, HPMC, pullulan or starch, in one embodiment the film forming polymer is HPMC and the capsule shell contains gellan. The amount of gellan in the capsule shell may be from 0.01 to 10 wt %, preferably 0.01 to 7 wt %, more preferably 0.1 to 7 wt %, even more preferably from 1 to 7 wt %, especially from 3 to 6 wt %, more especially from 4 to 6 wt %, the wt % being based on the weight of HPMC.

Examples

Materials and Abbreviations

[0093] capsules in the examples DRcaps Capsules of Capsugel, now a Lonza company, Lonza Ltd, Basel, Switzerland, were used, DRcaps have a HPMC based formulation with gellan gum, DRcaps capsules have delayed release properties. The capsules had the Licaps capsule design of Capsugel, now a Lonza company, Lonza Ltd, Basel, Switzerland. [0094] CFS Capsule Filling and Sealing [0095] CFS 1200 CFS 1200 of Capsugel, now a Lonza company, Lonza Ltd, Basel,

[0096] Switzerland, is a CFS machine for lab and pilot plant scale operation, operating speed of ca. 1200 capsules per hour. The CFS operates with three steps: fillingsealingdrying. Drying is done by blowing air of a predefined temperature. [0097] HPMC hydroxypropyl methylcellulose, also called hypromellose or Cellulose, 2-hydroxypropyl methyl ether or cellulose hydroxypropyl methyl ether, CAS 9004-65-3 [0098] IPA aqueous isopropanol 80 wt % [0099] lactic acid (S)-Lactic acid about 90%, EMPROVE EXPERT Ph Eur,BP,E 270, Merck KGaA, Darmstadt, Germany [0100] Technical Data sheet of Lactic acid 90% from Merck: 20 to 40 mPa*s at 20 C. Lactic acid viscosity (literature): 37 to 39 mPa*s at ambient temperature [0101] 21.2 mPa*s at 35 C. [0102] LEMS Liquid Encapsulation Microspray Sealing [0103] LEMS 70 LEMS70 is a LEMS System of Capsugel, now a Lonza company, Lonza Ltd, Basel, Switzerland, a CFS machine for production scale operation, operating speed of up to 55000 capsules per hour, capsule size range: sizes 000, 00e1, 00, Oel, 0, 1. 2, 3, 4 [0104] rpm rounds per minute

[0105] (A) Sealing Fluid: A Solution 40/40/20 (w/w/w) of Lactic Acid/Isopropanol/Water Sealing Fluid (A1)

[0106] For 100 g of sealing fluid solution: [0107] 44.44 g of lactic acid [0108] 50 g of IPA [0109] 5.56 g of demineralized water

[0110] Sealing fluid solutions was prepared by adding the three component following this order: Lactic acid, water and then IPA. The solution is then mixed with a magnetic stirrer.

[0111] The sealing fluid was used at ambient temperature to seal capsules.

[0112] (B) General Description of the Sealing

[0113] Two different sealing machines were used, the CFS 1200 and the LEMS 70.

[0114] CFS 1200 was used at a speed of ca. 1200 capsules per hour.

[0115] LEMS was used at a speed of ca. 40000 capsules per hour.

[0116] Capsules of size 0 were used in the examples.

[0117] (C) Leak Rate Detection

[0118] Sealed capsules were spread out on white paper sheets on trays and stored overnight (ca. 12 h) at ambient temperature and ambient pressure.

[0119] Then the trays were put into a vacuum chamber and vacuum of 250 mbar was applied in the vacuum chamber for 20 min. Thereafter the trays were taken out of the vacuum chamber and the capsules were then visually inspected on a light table to observe potential leaks which show as oily stains spread out under a leaking capsule in the paper sheet. Leak rate is given as % of leaking capsules of the total amount of capsules tested for leaking. The capsules may have been left on the paper sheets on the trays for 1 week and another determination of the leak rate by visual inspection may have been done.

[0120] In case of lab scale operation, such as on CFS 1200, leak rates of 0.5% or below are acceptable.

[0121] In case of pilot plant scale/production scale operation, such as on LEMS, leak rates of 0.05% or below are acceptable

[0122] (D) Viscosity

[0123] Apparatus to Measure Viscosity:

[0124] Viscosimeter BROOKFIELD DV-II+, AMETEK Brookfield, Middleboro, MA, USA, with Chamber SC4-13R and cylindrical spindle 18.

[0125] Temperature chamber has to be regulated by a water bath at 22 C.0.1 C.

[0126] Sealing fluid is introduced with a syringe in order to fill half of the viscosity chamber.

[0127] Then the spindle is introduced and chamber is completely filled up with the sealing fluid up to 1 mm from the rim. The absence of bubbles is checked to avoid error for viscosity measurement.

[0128] Viscosimeter speed is chosen to be the highest as possible to have the best measurement precision.

[0129] Viscosity is measured after 10 min.

[0130] Viscosity value=mean of 2 measurements

[0131] Details are given in table 6 and table 7.

TABLE-US-00001 TABLE 6 Viscosity Speed Viscosity Brookield at 22 C., Spindle 18 [mPa * s] [rpm] Sealing Fluid (A1) 9.1 +/ 2.9 100 Lactic Acid/isopropanol/H.sub.2O 40/40/20 (w/w/w) WO 2004/103338 A1 Example 6: 14 820 0.3 HPMC E50 6 parts by weight H.sub.2O 25 parts by weight Lactic acid 44 parts by weight Propan-2-ol 25 parts by weight Total 100 parts by weight

TABLE-US-00002 TABLE 7 (1) I II III Viscosity I II III [wt %] [wt %] [wt %] [mPa*s] acetic acid isopropanol 70 30 2.8 acetic acid isopropanol 50 50 2.85 acetic acid isopropanol H.sub.2O 50 30 20 3.7 lactic acid isopropanol H.sub.2O 40 30 30 7.05 lactic acid isopropanol H.sub.2O 40 20 40 6.25 lactic acid isopropanol H.sub.2O 50 20 30 8.05 lactic acid EtOH H.sub.2O 50 30 20 6.9 lactic acid EtOH H.sub.2O 40 36 24 5.6 lactic acid EtOH H.sub.2O 35 39 26 5.1 (1) Viscosity Brookield at 22 C., Spindle 18, speed 100 rpm

Example 1Sealing with CFS 1200

[0132] (1a) Filling with Oil

[0133] Capsules were filled in CFS 1200 with peanut oil. The viscosity of the peanut oil was very low (74.9 mPa*s at 22 C.Brookfield viscosity) which is especially prone to leak and therefore a good model for leak rate detection. Each capsule was filled with the same amount of oil. Capsules were then closed and were moved to the sealing position in and by the CFS 1200.

[0134] (1b) Sealing

[0135] Each capsule was sealed on CFS 1200 with 20 mg of sealing fluid per capsule, the sealing fluid having been prepared according to (A1), the sealing fluid was sprayed around the outward and open end of the gap provided by the overlap of the telescopically joined cap and body of the capsule.

[0136] No problems such as clogging of the sealing machine was observed.

[0137] (1c) Drying

[0138] Drying temperature in the CFS 1200 was 25 C.

[0139] (1d) Results

[0140] Leak Rate Detection was done according to (C). Results are shown in Table 1.

[0141] Before the vacuum chamber no leaks were detected.

TABLE-US-00003 TABLE 1 Leak Rate [%] Number of capsules After vacuum sealed chamber after 1 week 1062 0.0 0.0

[0142] The dimension, shape and stability of the capsules was not affected by the sealing.

Example 2Sealing with LEMS 70

[0143] (2a) Filling with Oil

[0144] Capsules were filled with sunflower oil. The viscosity of the sunflower oil was very low (53 mPa*s at 22 C.Brookfield viscosity) which is especially prone to leak and therefore a good model for leak rate detection. Each capsule was filled with the same amount of oil. Capsules were then closed.

[0145] (2b) Sealing

[0146] Each capsule was sealed in the LEMS 70 with 25 mg of sealing fluid per capsule, the sealing fluid having been prepared according to (A1), the sealing fluid was sprayed onto the capsule including spraying around the outward and open end of the gap provided by the overlap of the telescopically joined cap and body of the capsule.

[0147] No problems such as clogging of the sealing machine was observed.

[0148] (2c) Drying

[0149] Drying temperature in the LEMS 70 was 35 C.

[0150] (2d) Results

[0151] Leak Rate Detection was done according to (C). Results are shown in Table 2.

[0152] Before the vacuum chamber no leaks were detected.

TABLE-US-00004 TABLE 2 Leak Rate [%] Number of capsules After vacuum Run sealed chamber 1 12 492 0.00% 2 30 186 0.02% 3 32 490 0.01% 4 30 375 0.01% 5 32 800 0.03% 6 30 609 0.01% 7 33 066 0.01%

[0153] 7 repetitive runs resulted repeatedly in acceptable and comparable Leak Rates.

[0154] The dimension, shape and stability of the capsules was not affected by the sealing.

Example 3

[0155] Example 1 was repeated with the details given in tables 3 to 5. The sealing fluids were prepared according to (A) with the compositions given in the tables 3 to 5. Sealing was done with a CFS 1200 according to (B) and leak rate detection was done according to (C).

[0156] In each run no leaks were observed before the vacuum chamber.

[0157] No problems such as clogging of the sealing machine was observed.

[0158] All runs show acceptable leak rates.

[0159] The dimension, shape and stability of the capsules was not affected by the sealing.

TABLE-US-00005 TABLE 3 Sealing fluid (A2) Number Leak Rate Acetic acid/ of [%] isopropanol capsules After vacuum after Run (w/w) sealed chamber 1 week 3-20 70/30 443 0.2% N/A 3-21 50/50 105 0% N/A

TABLE-US-00006 TABLE 4 Sealing fluid (A3) Number Leak Rate (A3) Lactic acid/ of [%] EtOH/H.sub.2O capsules After vacuum after Run (w/w/w) sealed chamber 1 week 3-30 50/30/20 1212 0.0 0.0 3-31 40/36/24 573 0.0 0.0 3-32 35/39/26 557 0.0 0.0

TABLE-US-00007 TABLE 5 Sealing fluid (A4) Number Leak Rate Lactic acid/ of [%] isopropanol/H.sub.2O capsules After vacuum after Run (w/w/w) sealed chamber 1 week 3-40 40/30/30 475 0.2 0.2 (1) 3-41 40/20/40 549 0.2 0.2 (1) 3-42 50/20/30 1065 0.2 0.2 (1) (1) no additional leak after one week, that means the leak rate remains the same