Soft multi-chamber bag and method of using same

Abstract

A method for preparing pharmaceutical formulations in a single flexible multi-compartment bag is provided. [Solution] A pharmaceutical formulation is introduced in a liquid state into a first compartment of a flexible bag through a first port. The pharmaceutical formulation is freeze-dried in the first compartment of the flexible bag to obtain a freeze-dried pharmaceutical formulation. The flexible bag has a second compartment, the first compartment and the second compartment being separated by a breakable seal. The second compartment further contains a reconstitution solution for reconstituting the freeze-dried pharmaceutical formulation in the first compartment. A user can apply pressure to the flexible bag to break the seal and mix the freeze-dried pharmaceutical formulation with the reconstitution solution to administer the pharmaceutical formulation to a patient.

Description

[Technical Field]

[0001] Aspects of the present invention relate generally to flexible multi-compartment bags for use with pharmaceutical formulations. More specifically, aspects relate to methods, systems, and devices for the manufacture, storage, reconstitution, dilution, and administration to patients of lyophilized pharmaceutical formulations. [Background technology]

[0002] Lyophilization, or freeze-drying, is a technique applied to pharmaceutical preparations. The shelf life of pharmaceutical preparations that would be minimal in the liquid state can be extended and standardized through lyophilization. Lyophilization is a process that removes the liquid portion from a frozen sample by converting it directly to a vapor without the formation of a liquid intermediate. The main steps in lyophilization are freezing (from the liquid state to the solid state), primary drying (sublimation), and secondary drying (at elevated temperatures to remove the unfrozen liquid). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] US Patent No. 5,309,649 [Patent Document 2] US Patent No. 4,973,327 [Patent Document 3] US 6,517,526 B1 [Patent Document 4] US 7,776,022 B2 [Patent Document 5] CN 104443822 A Summary of the Invention

[0004] SUMMARY OF THE INVENTION The following presents a simplified summary of the disclosure in order to provide a basic understanding of some aspects described herein. This summary is not an extensive overview and is not intended to identify key or critical elements or to delineate the scope of the claims. The following summary merely presents various described aspects in a simplified form as a prelude to the more detailed description that is presented below.

[0005] This embodiment relates to a process, system, and apparatus for freeze-drying a pharmaceutical formulation in a flexible, multi-compartment bag. The freeze-dried pharmaceutical formulation can be stored and reconstituted in the same flexible, multi-compartment bag in which it was freeze-dried. By freeze-drying, storing, and reconstituting the pharmaceutical formulation in the same bag, the bag functions as a self-contained formulation ready for administration to a patient without the need for additional handling steps outside the flexible, multi-compartment bag. Advantages of the flexible, multi-compartment bag include reduced reconstitution time and errors during dilution, reconstitution, and handling of the pharmaceutical formulation, and the avoidance of accidental exposure to healthcare workers, thereby improving regulatory compliance.

[0006] Aspects of the present disclosure may include a method for preparing a pharmaceutical formulation in a flexible multi-compartment bag. The pharmaceutical formulation is introduced in a liquid state into a first compartment of the flexible bag through a first port. The pharmaceutical formulation is freeze-dried in the first compartment of the flexible bag to obtain a freeze-dried pharmaceutical formulation. The flexible bag has a second compartment, the first compartment and the second compartment being separated by a breakable seal. The second compartment further contains a reconstitution solution for reconstituting the freeze-dried pharmaceutical formulation in the first compartment. A user can apply pressure to the flexible bag to break the seal and mix the freeze-dried pharmaceutical formulation with the reconstitution solution to administer the pharmaceutical formulation to a patient.

[0007] Another aspect of the present disclosure is a method for manufacturing a semiconductor device comprising: a first compartment configured to hold a lyophilized pharmaceutical formulation; and a second compartment isolated from the first compartment and configured to hold a reconstitution solution for reconstituting the lyophilized pharmaceutical formulation in the first compartment; The pharmaceutical soft bag may include a The bag is a seal disposed between the first compartment and the second compartment, isolating and sealing the first compartment from the second compartment; It may further include: The first port is attached to the first compartment and is configured to introduce a pharmaceutical formulation into the first compartment and to allow the passage of water vapor from the pharmaceutical formulation during lyophilization of the pharmaceutical formulation. The second compartment is a second port attached to the second compartment and configured to introduce a reconstitution solution for reconstituting the lyophilized pharmaceutical formulation in the first compartment; may include: The seal can be broken by the medical professional to mix the lyophilized pharmaceutical formulation with the reconstitution solution.

[0008] In another aspect of the invention, the bag can be made from a material that can withstand autoclave sterilization at 121 degrees Celsius and freeze drying at -45 degrees Celsius.

[0009] More specifically, the present invention provides: [1] 1. A method for preparing a pharmaceutical formulation in a flexible multi-chamber bag, comprising: introducing the pharmaceutical formulation in a liquid state through a first port into a first compartment of the flexible bag; and freeze-drying the pharmaceutical formulation in the first compartment of the flexible bag to obtain a freeze-dried pharmaceutical formulation. Including, a method wherein the flexible bag has a second compartment, the first compartment and the second compartment being separated by a breakable seal; [2] The method of [1], further comprising the step of introducing a reconstituted solution into a second compartment of the flexible bag; [3] The method of [1], further comprising the step of introducing a gas into the first compartment and sealing the first port after the pharmaceutical formulation in the first compartment has been lyophilized; [4] applying a predetermined amount of pressure to the flexible bag to break the breakable seal between the first compartment and the second compartment; and mixing the reconstitution solution with the lyophilized pharmaceutical formulation in the first compartment to create a reconstituted pharmaceutical formulation. The method of [1], further comprising: [5] [4] The method of [4], further comprising administering the final pharmaceutical formulation to a patient through an administration port disposed in the flexible bag; [6] The method of [1], wherein a breakable seal is formed between the first compartment and the second compartment by joining the front surface of the flexible bag and the back surface of the flexible bag; [7] the breakable seal includes a weakness, where the breakable seal is not as wide as the remainder of the breakable seal; When pressure is applied to the flexible bag, failure of the frangible seal initiates at the weak point. [6] The method described; [8] [1] The bag according to [1], wherein the pharmaceutical preparation is a cytotoxic drug; [9] [8] The bag according to [8], wherein the cytotoxic agent is selected from the group consisting of azacitidine, belinstat, bendamustine, brentuximab vedotin, bleomycin, bortezomib, busulfan, carboplatin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, deferoxamine, doxorubicin, epirubicin hydrochloride, fludarabine, fotemustine, fulvestrant, gemcitabine, idarubicin, ifosfamide, irinotecan hydrochloride, ixabepilone, melphalan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, pentostatin, raltitrexed, romidepsin, temozolomide, thiotepa, topotecan, trabectedin, trastuzumab, and vinblastine;

[10] [2] The bag according to [2], wherein the reconstitution solution is 0.9% saline;

[11] The method according to [1], wherein the bag is made from a polyolefin / styrene block copolymer film;

[12] a first compartment configured to hold a lyophilized pharmaceutical formulation; a second compartment isolated from the first compartment and configured to hold a reconstitution solution for reconstituting the lyophilized pharmaceutical formulation in the first compartment; a seal disposed between the first compartment and the second compartment, isolating and sealing the first compartment from the second compartment; and a first port attached to the first compartment and configured to introduce the pharmaceutical formulation into the first compartment and to allow passage of water vapor from the pharmaceutical formulation during lyophilization of the pharmaceutical formulation; a pharmaceutical soft bag, including:

[13]

[12] The pharmaceutical bag of

[12] , further comprising a second port attached to the second compartment and configured to introduce a reconstitution solution into the second compartment for reconstituting the lyophilized pharmaceutical formulation in the first compartment;

[14]

[12] The pharmaceutical bag according to

[12] , wherein the seal is a connection between the front surface of the pharmaceutical bag and the back surface of the pharmaceutical bag;

[15]

[12] The pharmaceutical bag of

[12] , wherein the seal extends along the length of the pharmaceutical bag between the first compartment and the second compartment;

[16]

[12] The pharmaceutical bag of

[12] , wherein a predetermined amount of pressure applied to the pharmaceutical bag breaks the seal and connects the second compartment to the first compartment;

[17]

[12] The pharmaceutical bag of

[12] , wherein the seal further comprises a weakness that provides a point at which the seal will initially break when a predetermined amount of pressure is applied to the pharmaceutical bag;

[18]

[12] The pharmaceutical bag according to

[12] , wherein the pharmaceutical preparation is a cytotoxic drug;

[19]

[18] The pharmaceutical bag of

[19] , wherein the cytotoxic agent is selected from the group consisting of azacitidine, belinstat, bendamustine, brentuximab vedotin, bleomycin, bortezomib, busulfan, carboplatin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, deferoxamine, doxorubicin, epirubicin hydrochloride, fludarabine, fotemustine, fulvestrant, gemcitabine, idarubicin, ifosfamide, irinotecan hydrochloride, ixabepilone, melphalan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, pentostatin, raltitrexed, romidepsin, temozolomide, thiotepa, topotecan, trabectedin, trastuzumab, and vinblastine;

[20]

[12] The pharmaceutical bag according to

[12] , wherein the reconstitution solution is 0.9% saline; [twenty one]

[12] A pharmaceutical bag according to

[12] , which is made from a polyolefin / styrene block copolymer film; [twenty two]

[12] A pharmaceutical bag as described in

[12] that can withstand temperatures up to 121 degrees Celsius; [twenty three] A pharmaceutical bag as described in

[12] that can withstand temperatures of -45 degrees Celsius; [twenty four]

[12] The pharmaceutical bag of

[12] , wherein the second compartment further comprises an administration port for administering a reconstituted pharmaceutical formulation resulting from mixing the lyophilized pharmaceutical formulation with a reconstitution solution; [twenty five] Front film; Back film; an outer seal joining the front film to the back film around the periphery of the pharmaceutical bag; and A rupturable seal joining the front and back films inside the outer seal and defining a first compartment and a second compartment isolated from the first compartment. Including, the first compartment is configured to hold a lyophilized pharmaceutical formulation; the second compartment is configured to hold a reconstitution solution for reconstituting the lyophilized pharmaceutical formulation in the first compartment; when a predetermined amount of pressure is applied to the pharmaceutical flexible bag, the breakable seal breaks before the outer seal; Pharmaceutical soft bags; and

[26]

[25] The pharmaceutical soft bag according to

[25] , wherein the first compartment and the second compartment are defined by an outer seal and a breakable seal. [Brief explanation of the drawings]

[0010] Certain features of the present invention are illustrated by way of example, and not by way of limitation, in the accompanying drawings in which like numerals refer to like elements between the drawings, and in which:

[0011] [Figure 1] 1 shows one embodiment of a flexible, multi-compartment bag for holding a lyophilized pharmaceutical formulation and corresponding reconstitution solution. [Figure 2] 2 shows a cross-sectional view of one embodiment of a flexible multi-chamber bag taken along the 2-2 cross-sectional line in FIG. 1. [Figure 3] 1 shows a flow diagram of one embodiment of a method for preparing a pharmaceutical formulation in a flexible multi-chamber bag. [Figure 4]1 shows a flow diagram of one embodiment of a method for preparing a pharmaceutical formulation in a flexible multi-chamber bag. [Figure 5] 1 shows an embodiment of a flexible multi-compartment bag in which a pharmaceutical formulation is placed in the first compartment of the flexible multi-compartment bag. [Figure 6] 1 shows an embodiment of a flexible multi-compartment bag in which a pharmaceutical lyophilized (freeze-dried) formulation is placed in the first compartment of the flexible multi-compartment bag. [Figure 7] 1 shows an embodiment of a flexible multi-compartment bag in which a pharmaceutical lyophilized (freeze-dried) formulation is placed in a first compartment of the flexible multi-compartment bag and a reconstitution solution is placed in a second compartment of the flexible multi-compartment bag. [Figure 8] 1 shows an embodiment of a flexible multi-compartment bag containing a pharmaceutical lyophilized (freeze-dried) formulation in a first compartment of the flexible multi-compartment bag and a reconstitution solution in a second compartment of the flexible multi-compartment bag, where pressure is applied to the second compartment to break the seal and mix the lyophilized pharmaceutical formulation with the reconstitution solution. [Figure 9] 1 shows one embodiment of a flexible multi-compartment bag containing a reconstituted pharmaceutical formulation in operation. DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description The present invention will now be described in detail with reference to embodiments thereof illustrated in the accompanying drawings. In the accompanying drawings, like reference numerals are used to indicate identical or functionally similar elements. References to "one embodiment," "one embodiment," "one exemplary embodiment," etc. indicate that the described embodiment may include a particular feature, structure, or characteristic, but all embodiments may not necessarily include the particular feature, structure, or characteristic. Moreover, such phrases do not necessarily refer to the same embodiment. Furthermore, when a particular feature, structure, or characteristic is described in the context of one embodiment, it is believed to be within the knowledge of one skilled in the art to implement such feature, structure, or characteristic in the context of other embodiments, whether or not explicitly described.

[0013] The following examples are intended to illustrate, but not limit, the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in the art and obvious to those skilled in the art are within the spirit and scope of the invention.

[0014] This embodiment relates to a process, system, and apparatus for freeze-drying a pharmaceutical formulation in a flexible, multi-compartment bag. The freeze-dried pharmaceutical formulation can be stored and reconstituted in the same flexible, multi-compartment bag in which it was freeze-dried. By freeze-drying, storing, and reconstituting the pharmaceutical formulation in the same bag, the bag functions as a self-contained formulation ready for administration to a patient without the need for additional handling steps outside the flexible, multi-compartment bag. Advantages of the flexible, multi-compartment bag include reduced reconstitution time and errors during dilution, reconstitution, and handling of the pharmaceutical formulation, and the avoidance of accidental exposure to healthcare workers, thereby improving regulatory compliance.

[0015] Flexible multi-compartment bags can be used with some pharmaceutical preparations. For example, flexible multi-compartment bags may be advantageous for the preparation of cytotoxic and / or chemotherapeutic preparations. Examples of cytotoxic and antineoplastic compounds include at least azacitidine, belinstat, bendamustine, brentuximab vedotin, bleomycin, bortezomib, busulfan, carboplatin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, deferoxamine, doxorubicin, epirubicin hydrochloride, fludarabine, fotemustine, fulvestrant, gemcitabine, idarubicin, ifosfamide, irinotecan hydrochloride, ixabepilone, melphalan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, pentostatin, raltitrexed, romidepsin, temozolomide, thiotepa, topotecan, trabectedin, trastuzumab, and vinblastine. Cytotoxic drugs refer to a group of pharmaceuticals that contain chemicals that are toxic to cells, preventing them from replicating or growing, and are used to treat cancer and other disorders. Generally, cytotoxic drugs are manufactured in lyophilized form to extend the drug's shelf life, to facilitate drug transport, and for the health and well-being of medical professionals who handle and administer cytotoxic drugs to patients.

[0016] Other pharmaceutical preparations can be used with the multi-chamber bag. Examples of antibiotic compounds include at least amikacin, erythromycin, and mitomycin. Examples of antimitotic compounds include at least amphotericin, anidulafungin, flucytosine, fluconazole, isavuconazonium sulfate, micafungin, rifampicin, and voriconazole. Examples of antiviral compounds include at least acyclovir and ganciclovir. Examples of beta-blocking compounds include at least esmolol. Examples of antidote compounds include at least amifostine, dexrazoxane, and levoleucovorin calcium. Examples of immunomodulatory compounds include at least abatacept, aldesleukin, belimumab, degarelix, infliximab, mifamurtide, and tasonermin. Exemplary antibacterial compounds include at least amoxicillin, ampicillin, ampicillin / sulbactam, azithromycin, aztreonam, cefuroxime, clarithromycin, daptomycin, caspofungin, cephalothin, cefamandole, cefotaxime, cefazolin, cefepime, ceftazidime, cefoxitin, ceftobiprole medcaril, ceftaroline fosamil, chloramphenicol, dalbavacin hydrochloride, dalfopristin / quinupristin, doripenem, ertapenem, gentamicin, imipenem / cilastatin, meropenem, oritavancin diphosphate, oxacillin, piperacillin / tazobactam, pentamidine, tedizolid phosphate, teicoplanin, telavancin hydrochloride, tigecycline, and vancomycin. Examples of anti-inflammatory compounds include at least diclofenac, ibuprofen, and indomethacin. Examples of hemostatic compounds include at least alpha 1 antitrypsin, coagulation factor VII, coagulation factor VIII, coagulation factor IX, human antihemophilic prothrombin complex, gabexate, moroctocog alfa, nonacog alfa, octocog alfa, and simoctocog alfa.Examples of antiemetic compounds include at least fosaprepitant. Examples of antithrombotic compounds include at least alteplase, bivalirudin, cangrelor, epoprostenol, and urokinase. Examples of proton pump inhibitors include at least esomeprazole, omeprazole, and pantoprazole. Examples of antianxiety compounds include at least lorazepam. Examples of calcium channel blockers include at least diltiazem. Examples of detoxification compounds include at least pralidoxime. Examples of enzymes include at least agalsidase beta, alglucosidase alfa, alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase, taliglucerase alfa, and velaglucerase alfa. Examples of hormones include at least glucagon, levothyroxine sodium, menotropin, somatorelin, somatostatin, somatropin, and urofollitropin. Examples of anti-angiogenic compounds include at least verteporfin. Examples of compounds for treating bone diseases include at least zoledronic acid. Examples of cardiac therapeutic compounds include at least nesiritide. Examples of diagnostic hormones include at least secretin and somatorelin.

[0017] Because of the toxicity of cytotoxic agents, occupational exposure to healthcare workers presents a significant risk, especially if control measures are inadequate. Control measures can include the use of protective clothing, devices, and equipment to prevent accidental exposure. Healthcare workers can be exposed to cytotoxic agents by inhalation, through skin contact, or orally.

[0018] Inhalation exposure can occur through droplets, particles, and vapors when aerosols are created. Safety cabinets may not be able to remove vapors from the atmosphere because the molecular diameter of vapors is smaller than that of particles. Skin exposure can occur when healthcare workers touch contaminated surfaces during drug preparation, administration, or disposal. Contamination can be found on relevant work surfaces throughout the hospital medication system (the facility's process flow of cytotoxic drugs from initial delivery to final waste disposal) and is not strictly limited to the drug preparation and administration areas. Oral exposure can occur through hand-to-mouth contact.

[0019] Aspects of the present disclosure relate to a bag configured to lyophilize a pharmaceutical formulation within a compartment of the bag. In some aspects, the bag is configured to hold a reconstitution solution within another compartment of the bag and to allow mixing of the lyophilized pharmaceutical formulation with the reconstitution solution within the bag. In some aspects, the bag is configured to allow administration of the reconstituted pharmaceutical formulation from the bag to a patient. In some aspects, the bag advantageously can maintain the pharmaceutical formulation within the bag without further manipulation of the pharmaceutical formulation outside of the bag after the pharmaceutical formulation is introduced into the bag.

[0020] FIG. 1 illustrates an exemplary embodiment of a flexible, multi-compartment bag 100. While FIG. 1 illustrates the bag 100 with two compartments, the present disclosure is not so limited. The bag 100 may have multiple compartments for holding various components and solutions. The bag 100 may include an outer seal 102 extending around the bag 100. The outer seal 102 may provide an oxygen and water vapor seal to prevent contamination of components stored in the bag 100 (e.g., pharmaceutical formulations, reconstitution solutions, etc.). The outer seal 102 defines the outer boundaries of a first compartment 110 and a second compartment 120. In one embodiment, as shown in FIG. 1, the bag 100 includes a first compartment 110 for holding and lyophilizing a pharmaceutical formulation. The first compartment 110 may include a port 112 for sterilely introducing the pharmaceutical formulation into the first compartment 110. The port 112 may be used in lyophilization procedures to allow the passage of water vapor from the pharmaceutical formulation. The first compartment 110 may have a volume suitable for lyophilizing the pharmaceutical formulation. For example, the first compartment 110 may have a volume of 50 ml. Other suitable volumes may also be used.

[0021] Bag 100 may further include a second compartment 120 for holding a reconstituted solution or solvent. Second compartment 120 may include one or more ports for introducing the reconstituted solution into second compartment 120 and for administering the reconstituted pharmaceutical formulation to a patient. For example, port 122 may be used to sterilely introduce the reconstituted solution into second compartment 120. Second compartment 120 may further include multiple administration ports 124 and 126. The types of ports 124 and 126 attached to second compartment 120 may be based on customer and healthcare professional preferences. For example, in operation, administration ports 124 and 126 are usable by healthcare professionals to administer the reconstituted pharmaceutical formulation to a patient, for example, via intravenous therapy. As envisioned, bag 100 may be used by any suitable individual, but for simplicity, this disclosure will refer to the user as a healthcare professional. In one embodiment, the second compartment 120 can be sized to match the first compartment 110 to provide a sufficient amount of reconstitution solution to reconstitute the pharmaceutical formulation in the first compartment 110. In one embodiment, the second compartment 120 can have a volume greater than the volume of the first compartment 110. For example, the second compartment 120 can have a volume of 500 ml. Other suitable volumes may be used.

[0022] Bag 100 may further include a seal 130 that separates and defines first compartment 110 and second compartment 120. Seal 130 maintains the integrity of the lyophilized pharmaceutical formulation and reconstitution solution, preventing the reconstitution solution from unintentionally passing through the lyophilized pharmaceutical formulation, or vice versa, before the appropriate time. FIG. 1 shows seal 130 extending along the length of bag 100 from the top to the bottom of bag 100. Alternatively, seal 130 may extend along only a portion of the length of bag 100. For example, in one embodiment, seal 130 may extend from outer seal 102 to inner seal 104 of bag 100, as shown in FIGS. 5-7. However, the geometry of seal 130 is not limited thereto. In another embodiment, seal 130 may be curved.

[0023] In one embodiment, the bag 100 can be fabricated from a tubular film or cut as a double-wrapped film at a desired width. For example, as shown in FIG. 2 , the bag 100 can include a front film 210 and a back film 220 joined together. The front film 210 and the back film 220 can be joined together at their edges to create an outer seal 102. The outer seal 102 can be created by sealing the front film 210 and the back film 220 using a predetermined temperature and a predetermined amount of pressure. The outer seal 102 is created to be unbreakable, at least during normal operation. Furthermore, the front film 210 and the back film 220 can be joined together inside the outer seal 102 to define a seal 130. The seal 130 is created by sealing the front film 210 and the back film 220 using a predetermined temperature and a predetermined amount of pressure. In this manner, the seal 130 can define a connection between the front film 210 and the back film 220. The seal 130 is created to be breakable. The front film 210 and the back film 220 can be joined together through heat sealing, radio frequency welding, molding, and other suitable techniques. Figure 2 shows a cross-sectional view of the bag 100 taken along section line 2-2 of Figure 1. The 2-2 section line intersects the outer seal 102, the first compartment 110, the seal 130, and the second compartment 120.

[0024] In one embodiment, the seal 130 can be made from the same material as the entire bag 100 (e.g., the front film 210 and the back film 220). Because the bag 100 and the seal 130 are made from the same material, other materials do not come into contact with the pharmaceutical formulation, thereby avoiding contamination. The seals 130 can be placed in various locations on the bag 100 to form at least two compartments in the bag 100. If the bag 100 includes additional compartments, the bag 100 can include additional seals to isolate and define the compartment geometries. The seal 130 can be breached by applying a predetermined amount of pressure to the bag 100. For example, pressure can be applied to the second compartment 120 by a medical professional's hand. The amount of pressure required to breach the seal 130 can be in the range of 40 to 60 kgf. In this manner, the seal 130 becomes a breachable seal. As shown, for example, in FIG. 8 , to extend the shelf life of a freeze-dried pharmaceutical formulation, a healthcare professional can apply pressure when the healthcare professional is ready to administer the pharmaceutical formulation to a patient. When the seal 130 is breached, the reconstitution solution and the freeze-dried pharmaceutical formulation mix to produce a reconstituted pharmaceutical formulation. The seal 130 can have a width of 5-15 mm or 8-12 mm. The wider the seal 130, the stronger the seal 130 and the greater the pressure required to breach it. The seal 130 is designed to withstand a predetermined amount of pressure before breaching. For example, during shipping of a flexible bag, the seal 130 may be subjected to pressure and / or force during normal shipping procedures. The seal 130 is designed to maintain its integrity under a relatively small amount of pressure (e.g., less than 40 kgf), and therefore, the seal 130 will not breach during shipping until a predetermined amount of pressure is applied.

[0025] The seal 130 can be bonded to create a weakness 132 in the seal 130, so that the weakness 132 breaks first when pressure is applied to the bag 100. The seal 130 can include multiple weaknesses 132 along the length of the seal 130. The weakness 132 can have a smaller width than the rest of the seal 130. For example, the weakness 132 can have a width of 5-8 mm.

[0026] In one embodiment, the seal 130 may include a valve between the first compartment 110 and the second compartment 120 that prevents the passage of the reconstitution solution until the medical professional is ready to administer the pharmaceutical formulation.

[0027] The bag 100 can be made from a material that provides a barrier to oxygen and water vapor. The material may also be able to withstand the temperature limits of autoclave sterilization and lyophilization. For example, the material for the bag 100 can withstand autoclave sterilization at 121 degrees Celsius and freeze-drying at -45 degrees Celsius without the material degrading and leaching into the pharmaceutical formulation and reconstitution solution in the bag. Other aspects of the material include flexibility, which makes the bag 100 less likely to be crushed and easier to transport. The material may be transparent, allowing medical personnel to easily view the inside of the bag 100 to confirm that lyophilization and reconstitution have occurred and to see how much of the reconstituted pharmaceutical formulation is still present in the bag 100 during administration of the pharmaceutical formulation.

[0028] In one embodiment, bag 100 comprises a polyolefin / styrene block copolymer-based film. The material used in bag 100 meets all requirements mandated by U.S. and European pharmaceutical regulations, the SFDA standard "Registration standard for imported pharmaceutical packaging materials" (China), the international standard ISO 15747 "Plastics containers for intravenous injection," and the international standard ISO 10993 "Biological Evaluation of medical devices."

[0029] Each of the ports 112, 122, 124, and 126 may include a connector 114 and tubing 116. The connector 114 allows the ports 112, 122, 124, and 126 to be sealed and allows medical personnel and / or manufacturers to attach equipment for introducing and extracting solutions from the compartments. Various different types of connectors 114 can be used to expand the types of equipment available with the connectors 114. The tubing 116 allows for the passage of liquids or gases from the external environment to the compartments or vice versa. The tubing can be made from a polyolefin / styrene block copolymer co-extruded to the desired dimensions. The tubing can also be made from any other suitable material. The connections can be made from polypropylene and polycarbonate or any other suitable material. The ports 112, 122, 124, and 126 can withstand autoclave sterilization at 121 degrees Celsius and freeze-drying at -45 degrees Celsius. The outer diameter of the tubing can be 8.1 mm ± 0.08 mm, and the thickness of the tubing can be 1.0 mm ± 0.08 mm. In one embodiment, the materials used for ports 112, 122, 124, and 126 comply with all requirements mandated by U.S. and European pharmaceutical regulations, SFDA standard "Registration Standard for Imported Pharmaceutical Packaging Materials" (China), International Standard ISO 15747 "Plastic Containers for Intravenous Injection," and International Standard ISO 10993 "Biological Evaluation of Medical Devices."

[0030] Bag 100 may further include a label area 140 that is used to display available information, such as mandatory information that may be required by law, on bag 100. Additionally, label area 140 may include a barcode, QR code, RFID, etc., for easy identification of the pharmaceutical formulation, dosage details, warnings, potential adverse reactions, patient information, etc.

[0031] Bag 100 may further include a through-hole 150 in outer seal 102. Through-hole 150 may be utilized by a medical professional to attach bag 100 to an intravenous stand to facilitate administration of the reconstituted pharmaceutical formulation to a patient.

[0032] 3 shows a flow diagram of one embodiment of a method for preparing a pharmaceutical formulation in a bag 100. The method includes steps S310 of introducing the pharmaceutical formulation into a first compartment 110, S320 of lyophilizing the pharmaceutical formulation in the first compartment 110, S330 of introducing a reconstitution solution into the second compartment 120, and S340 of breaking the seal 130 and mixing the reconstitution solution with the lyophilized pharmaceutical formulation. Each step is described in further detail below.

[0033] In step S310, a predetermined amount of pharmaceutical formulation 500 of known concentration is sterilely introduced into the first compartment 110 of the bag 100 through port 112. For example, the pharmaceutical formulation may be passed through a sterile filter. The amount and concentration of the pharmaceutical formulation are required to calculate the dilution and reconstitution rates of the pharmaceutical formulation after lyophilization. FIG. 5 shows the pharmaceutical formulation 500 in the first compartment 110. Arrow 502 indicates that the pharmaceutical formulation 500 passes through port 112. The pharmaceutical formulation 500 may be in a liquid state. Once the pharmaceutical formulation 500 is in the first compartment 110, the port 112 is closed with a sterile stopper, allowing the bag 100 to be placed in a freeze-dryer. The sterile stopper does not completely close the port 112, leaving a space necessary to allow the passage of vapor during the freeze-drying process. The bag 100 is configured to withstand the conditions (e.g., temperature, pressure, etc.) of the freeze-dryer.

[0034] In step S320, the bag 100, along with other bags also containing pharmaceutical formulation 500, is placed on a tray in a freeze-dryer, if necessary. The bag 100 can be oriented in a vertical or slightly tilted vertical position with the port 112 facing up, and the bottom of the bag 100 can be secured to the tray. With the port 112 facing up, the port 112 allows the passage of water vapor from the pharmaceutical formulation during the freeze-drying procedure, preventing leakage of the pharmaceutical formulation during freeze-drying. Once all bags are securely positioned, the freeze-drying process can begin. Table 1, shown below, provides data related to an exemplary freeze-drying process for freeze-drying a pharmaceutical formulation. The temperature, time, and pressure can vary according to the type of pharmaceutical formulation placed in the bag 100. FIG. 6 shows the bag 100 containing the freeze-dried pharmaceutical formulation 600 after the freeze-drying process is complete.

[0035] [Table 1]

[0036] In S330, a predetermined amount of sterile reconstitution solution is aseptically introduced into the second compartment 120 through port 122. The amount of reconstitution solution introduced into the second compartment 120 depends on the desired dilution of the pharmaceutical formulation 500 for administration to the patient. FIG. 7 shows the reconstitution solution 700 in the second compartment 120. Arrow 702 indicates that the reconstitution solution 700 passes through port 122. The reconstitution solution 700 can be sterile 0.9% saline or any other solution suitable for reconstituting and diluting the pharmaceutical formulation 500. Other examples of reconstitution solutions include water, alcohol-based solutions, etc. Examples of dilution solutions include saline, dextrose solution, Ringer's solution, etc.

[0037] In one embodiment, step S330 can be performed when bag 100 is in multiple different positions. For example, reconstituted solution 700 can be introduced into second compartment 120 while bag 100 is still in the freeze-dryer. In another example, bag 100 can be removed from the freeze-dryer and reconstituted solution 700 can be introduced into the second compartment at a preparation facility prior to storage and transport under refrigerated and sterile conditions.

[0038] In S340, the healthcare professional can reconstitute and appropriately dilute the lyophilized pharmaceutical formulation 600 into a reconstituted pharmaceutical formulation 900 by mixing the reconstitution solution 700 with the lyophilized pharmaceutical formulation 600. The healthcare professional can manually apply pressure to the bag 100, for example, to the second compartment 120, to break the seal 130, as shown in FIG. 8. Because the bag 100 is flexible, when the healthcare professional squeezes the bag, pressure is generated within the bag 100 and applied to the seals 102, 104, and 130. The outer seal 102 and inner seal 104 are stronger than the seal 130 separating the first compartment 110 and the second compartment 120, and therefore the seal 130 will break before the outer seal 102 and inner seal 104.

[0039] Upon application of a predetermined amount of pressure (e.g., 40-60 kgf) to bag 100, seal 130 breaks, and first compartment 110 and second compartment 120 become a single compartment for mixing lyophilized pharmaceutical formulation 600 and reconstitution solution 700. In one embodiment, because the second compartment contains a liquid and first compartment 110 contains the lyophilized formulation and a gas, a medical professional can create more pressure by applying pressure to second compartment 120 rather than first compartment 110. Additionally, seal 130 may include a weakness 132 at which failure of seal 130 begins.

[0040] 4 shows another exemplary flow diagram of a method for preparing a pharmaceutical formulation in one bag 100. The method includes steps S410 of introducing the pharmaceutical formulation into the first compartment 110, S420 of lyophilizing the pharmaceutical formulation in the first compartment 110, S430 of closing the port 112 to the first compartment 110 via gas injection, S440 of introducing a reconstitution solution into the second compartment 120, S450 of breaking the seal 130 and mixing the reconstitution solution with the lyophilized pharmaceutical formulation, and S460 of administering the reconstituted pharmaceutical formulation to a patient. Each step is described in further detail below.

[0041] Steps S410, S420, S440, and S450 are similar to steps S310, S320, S330, and S340 described above with respect to the method of FIG. 3. In S430, once the pharmaceutical formulation 500 has been lyophilized, the integrity of the lyophilized pharmaceutical formulation 600 can be maintained by permanently closing the port 112. For example, the lyophilized pharmaceutical formulation 600 can be contaminated by the external environment, e.g., oxygen, water vapor, etc.; therefore, sealing the first compartment 110 can help maintain the integrity of the lyophilized pharmaceutical formulation 600. The port 112 can be sealed by gas injection. The lyophilization vacuum can be broken by an insufflation gas under a light vacuum, and the gas is introduced into the first compartment 110. In one embodiment, the insufflation gas is nitrogen. If the pharmaceutical formulation is not sensitive to oxygen, compressed air can be used as the insufflation gas. This process maintains the sterility of the first compartment 110 and avoids oxidation of the lyophilized pharmaceutical formulation 600 .

[0042] In S460, after the healthcare professional reconstitutes pharmaceutical formulation 900, the healthcare professional can administer reconstituted pharmaceutical formulation 900 to a patient. Reconstituted pharmaceutical formulation 900 can be administered in several ways. For example, FIG. 9 shows reconstituted pharmaceutical formulation 900 being administered via intravenous therapy. Perforation 150 in bag 100 allows the healthcare professional to hang bag 100 from an intravenous stand, and administration ports 124 and 126 allow the healthcare professional to attach bag 100 to standard intravenous equipment for treatment.

[0043] Additionally, bag 100 can be sterilized in an autoclave at the pharmaceutical preparation manufacturing facility, as the material of bag 100 allows bag 100 to withstand autoclave sterilization at 121 degrees Celsius.

[0044] The method of lyophilizing, storing, and reconstituting a pharmaceutical formulation in the same flexible bag may have one or more advantages. For example, bag 100 is a ready-to-administer formulation requiring little or no manipulation by healthcare professionals. Lyophilizing the pharmaceutical formulation increases the shelf life of the pharmaceutical formulation. Storing the reconstitution solution in the second compartment prepares the pharmaceutical formulation for proper dilution and reconstitution, thereby avoiding potential errors in calculating reconstitution and dilution ratios. After the pharmaceutical formulation is introduced, it remains in the bag until it is administered, avoiding further manipulation of the pharmaceutical formulation outside the bag. Particularly if the pharmaceutical formulation is a toxic drug, such as a cytotoxic drug, further manipulation could result in contamination of the formulation and / or safety concerns for healthcare professionals. Retaining the pharmaceutical formulation in one bag and sealing the first compartment from the outside environment avoids potential contamination of the pharmaceutical formulation.

[0045] An embodiment of the invention may relate to a method of preparing a pharmaceutical formulation in a flexible multi-compartment bag, the method comprising the steps of introducing the pharmaceutical formulation in a liquid state through a first port into a first compartment of the flexible bag, and lyophilizing the pharmaceutical formulation in the first compartment of the flexible bag to obtain a lyophilized pharmaceutical formulation, the flexible bag having a second compartment, the first and second compartments being separated by a breakable seal.

[0046] In any of the various embodiments described herein, the method can further include introducing a reconstituted solution into a second compartment of the flexible bag.

[0047] In any of the various embodiments described herein, the method may further include, after the pharmaceutical formulation in the first compartment is lyophilized, introducing a gas into the first compartment and sealing the first port.

[0048] In any of the various embodiments described herein, the method may further include applying a predetermined amount of pressure to the flexible bag to break the breakable seal between the first compartment and the second compartment, and mixing a reconstitution solution and the lyophilized pharmaceutical formulation in the first compartment to create a reconstituted pharmaceutical formulation.

[0049] In any of the various aspects described herein, the method can further include administering the final pharmaceutical formulation to the patient through an administration port disposed in the flexible bag.

[0050] In any of the various embodiments described herein, a breakable seal is formed between the first compartment and the second compartment by joining the front surface of the flexible bag and the back surface of the flexible bag.

[0051] In any of the various aspects described herein, the breakable seal includes a weakness where the breakable seal is not as wide as the remainder of the breakable seal, and where failure of the breakable seal begins when pressure is applied to the flexible bag.

[0052] In any of the various embodiments described herein, the pharmaceutical agent is a cytotoxic agent.

[0053] In any of the various aspects described herein, the cytotoxic agent is selected from the group consisting of azacitidine, belinstat, bendamustine, brentuximab vedotin, bleomycin, bortezomib, busulfan, carboplatin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, deferoxamine, doxorubicin, epirubicin hydrochloride, fludarabine, fotemustine, fulvestrant, gemcitabine, idarubicin, ifosfamide, irinotecan hydrochloride, ixabepilone, melphalan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, pentostatin, raltitrexed, romidepsin, temozolomide, thiotepa, topotecan, trabectedin, trastuzumab, and vinblastine.

[0054] In any of the various embodiments described herein, the reconstitution solution is 0.9% saline.

[0055] In any of the various embodiments described herein, the bag is made from a polyolefin / styrene block copolymer based film.

[0056] Some embodiments include: a first compartment configured to hold a lyophilized pharmaceutical formulation; a second compartment separated from the first compartment and configured to hold a reconstitution solution for reconstituting the lyophilized pharmaceutical formulation in the first compartment; a seal disposed between the first compartment and the second compartment, isolating and sealing the first compartment from the second compartment; and a first port attached to the first compartment and configured to introduce the pharmaceutical formulation into the first compartment and to allow passage of water vapor from the pharmaceutical formulation during lyophilization of the pharmaceutical formulation; The pharmaceutical soft bag may include

[0057] In any of the various aspects described herein, the bag may include: a second port attached to the second compartment and configured to introduce a reconstitution solution into the second compartment for reconstituting the lyophilized pharmaceutical formulation in the first compartment; It may further include:

[0058] In any of the various aspects described herein, the seal is the connection between the front of the pharmaceutical bag and the back of the pharmaceutical bag.

[0059] In any of the various embodiments described herein, the seal extends along the length of the pharmaceutical bag between the first and second compartments.

[0060] In any of the various embodiments described herein, a predetermined amount of pressure applied to the pharmaceutical bag breaks the seal, connecting the second compartment to the first compartment.

[0061] In any of the various aspects described herein, the seal further includes a weakness that provides a point of initial rupture when a predetermined amount of pressure is applied to the pharmaceutical bag.

[0062] In any of the various embodiments described herein, the pharmaceutical agent is a cytotoxic agent.

[0063] In any of the various aspects described herein, the cytotoxic agent is selected from the group consisting of azacitidine, belinstat, bendamustine, brentuximab vedotin, bleomycin, bortezomib, busulfan, carboplatin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, deferoxamine, doxorubicin, epirubicin hydrochloride, fludarabine, fotemustine, fulvestrant, gemcitabine, idarubicin, ifosfamide, irinotecan hydrochloride, ixabepilone, melphalan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, pentostatin, raltitrexed, romidepsin, temozolomide, thiotepa, topotecan, trabectedin, trastuzumab, and vinblastine.

[0064] In any of the various embodiments described herein, the reconstitution solution is 0.9% saline.

[0065] In any of the various embodiments described herein, the pharmaceutical bag is made from a polyolefin / styrene block copolymer based film.

[0066] In any of the various embodiments described herein, the pharmaceutical bag is resistant to 121 degrees Celsius.

[0067] In any of the various embodiments described herein, the pharmaceutical bag is resistant to temperatures of -45 degrees Celsius.

[0068] In any of the various embodiments described herein, the second compartment further comprises an administration port for administering a reconstituted pharmaceutical formulation resulting from mixing the lyophilized pharmaceutical formulation with a reconstitution solution.

[0069] Some embodiments include: a front film, a back film, an outer seal joining the front film to the back film around the periphery of the pharmaceutical bag; and A rupturable seal joining the front and back films inside the outer seal and defining a first compartment and a second compartment isolated from the first compartment. The flexible pharmaceutical bag may include a first compartment configured to hold a lyophilized pharmaceutical formulation and a second compartment configured to hold a reconstitution solution for reconstituting the lyophilized pharmaceutical formulation in the first compartment, wherein when a predetermined amount of pressure is applied to the flexible pharmaceutical bag, the breakable seal breaks before the outer seal.

[0070] In any of the various embodiments described herein, the first compartment and the second compartment are defined by an outer seal and a rupturable seal.

[0071] It should be appreciated that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections may disclose one or more, but not all, exemplary aspects of the invention contemplated by the inventors, and therefore are not intended to limit the scope of the invention and the appended claims in any way.

[0072] The above description of specific embodiments fully reveals the general nature of the present invention, so that others, applying knowledge within the skill of the art, can readily modify and / or adapt such specific embodiments for various applications without undue experimentation and without departing from the general concept of the present invention. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology used herein is for the purpose of description, not limitation, and, accordingly, those skilled in the art should interpret the phraseology or terminology used herein in light of that teaching and guidance.

[0073] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents. [Explanation of symbols]

[0074] 100 bags 102 Outer seal 104 Inner seal 110 First Chamber Port 112 114 Connector 116 tube 120 Second Chamber Port 122 124 port Port 126 130 stickers 132 Weak spot 140 Label Area 150 holes 500 Pharmaceutical Preparations 600 Lyophilized pharmaceutical preparations 700 Reconstituted Solution 900 Reconstituted Pharmaceutical Preparations

Claims

1. 1. A method for preparing a pharmaceutical formulation in a flexible multi-chamber bag, comprising: introducing the pharmaceutical formulation in a liquid state through a first port into a first compartment of the flexible bag; and freeze-drying the pharmaceutical formulation in the first compartment of the flexible bag to obtain a freeze-dried pharmaceutical formulation. Including, The method, wherein the flexible bag has a second compartment, and the first and second compartments are separated by a breakable seal.

2. 10. The method of claim 1, further comprising introducing a reconstituted solution into a second compartment of the flexible bag.

3. 10. The method of claim 1, further comprising the step of introducing a gas into the first compartment and sealing the first port after the pharmaceutical formulation in the first compartment is lyophilized.

4. applying a predetermined amount of pressure to the flexible bag to break the breakable seal between the first compartment and the second compartment; and mixing the reconstitution solution with the lyophilized pharmaceutical formulation in the first compartment to create a reconstituted pharmaceutical formulation.

10. The method of claim 1, further comprising:

5. 5. The method of claim 4, further comprising administering the final pharmaceutical formulation to the patient through an administration port disposed in the flexible bag.

6. 10. The method of claim 1, wherein a breakable seal is formed between the first compartment and the second compartment by joining the front surface of the flexible bag and the back surface of the flexible bag.

7. the breakable seal includes a weakness, where the breakable seal is not as wide as the remainder of the breakable seal; 7. The method of claim 6, wherein failure of the frangible seal initiates at the weak point when pressure is applied to the flexible bag.

8. 10. The bag of claim 1, wherein the pharmaceutical agent is a cytotoxic drug.

9. 9. The bag of claim 8, wherein the cytotoxic agent is selected from the group consisting of azacitidine, belinstat, bendamustine, brentuximab vedotin, bleomycin, bortezomib, busulfan, carboplatin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, deferoxamine, doxorubicin, epirubicin hydrochloride, fludarabine, fotemustine, fulvestrant, gemcitabine, idarubicin, ifosfamide, irinotecan hydrochloride, ixabepilone, melphalan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, pentostatin, raltitrexed, romidepsin, temozolomide, thiotepa, topotecan, trabectedin, trastuzumab, and vinblastine.

10. 3. The bag of claim 2, wherein the reconstitution solution is 0.9% saline.

11. 10. The method of claim 1, wherein the bag is made from a polyolefin / styrene block copolymer based film.

12. a first compartment configured to hold a lyophilized pharmaceutical formulation; a second compartment isolated from the first compartment and configured to hold a reconstitution solution for reconstituting the lyophilized pharmaceutical formulation in the first compartment; a seal disposed between the first compartment and the second compartment, isolating and sealing the first compartment from the second compartment; and a first port attached to the first compartment and configured to introduce the pharmaceutical formulation into the first compartment and to allow passage of water vapor from the pharmaceutical formulation during lyophilization of the pharmaceutical formulation; 1. A pharmaceutical soft bag comprising:

13. 13. The pharmaceutical bag of claim 12, further comprising a second port attached to the second compartment and configured to introduce a reconstitution solution into the second compartment for reconstituting the lyophilized pharmaceutical formulation in the first compartment.

14. 13. The pharmaceutical bag of claim 12, wherein the seal is a connection between a front surface of the pharmaceutical bag and a back surface of the pharmaceutical bag.

15. 13. The pharmaceutical bag of claim 12, wherein the seal extends along the length of the pharmaceutical bag between the first and second compartments.

16. 13. The pharmaceutical bag of claim 12, wherein a predetermined amount of pressure applied to the pharmaceutical bag breaks the seal and connects the second compartment to the first compartment.

17. 13. The pharmaceutical bag of claim 12, wherein the seal further comprises a weakness that provides a point of initial rupture when a predetermined amount of pressure is applied to the pharmaceutical bag.

18. 13. The pharmaceutical bag of claim 12, wherein the pharmaceutical agent is a cytotoxic drug.

19. 19. The pharmaceutical bag of claim 18, wherein the cytotoxic agent is selected from the group consisting of azacitidine, belinstat, bendamustine, brentuximab vedotin, bleomycin, bortezomib, busulfan, carboplatin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, deferoxamine, doxorubicin, epirubicin hydrochloride, fludarabine, fotemustine, fulvestrant, gemcitabine, idarubicin, ifosfamide, irinotecan hydrochloride, ixabepilone, melphalan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, pentostatin, raltitrexed, romidepsin, temozolomide, thiotepa, topotecan, trabectedin, trastuzumab, and vinblastine.

20. 13. The pharmaceutical bag of claim 12, wherein the reconstitution solution is 0.9% saline.

21. 13. The pharmaceutical bag of claim 12, made from a polyolefin / styrene block copolymer based film.

22. 13. The pharmaceutical bag of claim 12, which is resistant to 121 degrees Celsius.

23. 13. The pharmaceutical bag of claim 12, which is resistant to temperatures of -45 degrees Celsius.

24. 13. The pharmaceutical bag of claim 12, wherein the second compartment further comprises an administration port for administering a reconstituted pharmaceutical formulation resulting from mixing the lyophilized pharmaceutical formulation with a reconstitution solution.

25. Front film; Back film; an outer seal joining the front film to the back film around the periphery of the pharmaceutical bag; and A rupturable seal joining the front and back films inside the outer seal and defining a first compartment and a second compartment isolated from the first compartment. Including, the first compartment is configured to hold a lyophilized pharmaceutical formulation; the second compartment is configured to hold a reconstitution solution for reconstituting the lyophilized pharmaceutical formulation in the first compartment; when a predetermined amount of pressure is applied to the pharmaceutical flexible bag, the breakable seal breaks before the outer seal; Pharmaceutical soft bags.

26. 26. The pharmaceutical soft bag of claim 25, wherein the first compartment and the second compartment are defined by an outer seal and a breakable seal.

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