System for the manufacture of a Pulsincap dosage form containing lovastatin and colesevelam for the treatment of hypercholesterolemia

Abstract

A system for manufacturing a Pulsincap dosage form containing lovastatin and colesevelam for the treatment of hypercholesterolemia, comprising: a) a fungal cultivation facility configured to cultivate mangrove-associated marine fungi from the group consisting of Aspergillus sp., Penicillium sp., Rhizophus sp. and Fusarium sp. in production media to produce the metabolite lovastatin; b) a microsphere preparation plant for the production of floating lovastatin microspheres using ionotropic gelation technology with chitosan, sodium alginate and calcium carbonate; c) a granulation plant for the production of colesevelam granules using explosives from the group consisting of croscarmellose and microcrystalline cellulose; d) a capsule coating unit configured to coat the capsule body with cellulose acetate phthalate (CAP); and e) a stopper preparation unit configured to prepare hydrogel stoppers and coat them with ethylcellulose.

Description

AREA OF INVENTION

[0001] The present disclosure relates to a system for the manufacture of a Pulsincap dosage form containing lovastatin and colesevelam for the treatment of hypercholesterolemia. BACKGROUND OF THE INVENTION

[0002] Hypercholesterolemia, characterized by elevated LDL cholesterol levels, is a significant risk factor for life-threatening cardiovascular diseases, including heart attacks. Conventional treatment approaches utilize statins such as lovastatin, which inhibit cholesterol synthesis in the liver, and bile acid sequestrants such as colesevelam hydrochloride, which reduce cholesterol absorption in the intestine.

[0003] While low-dose combination therapy with colesevelam hydrochloride and lovastatin has been shown to effectively lower LDL cholesterol in patients with primary hypercholesterolemia, monotherapy with these drugs shows only limited efficacy. Lovastatin alone lowers LDL cholesterol by approximately 22% (39 mg / dL), whereas colesevelam alone achieves a reduction of only 7% (13 mg / dL).

[0004] Furthermore, existing formulations fail to release active ingredients at the optimal site of action according to the circadian rhythm, leading to suboptimal therapeutic outcomes and undesirable side effects. Conventional constant-release formulations, which follow zero-order kinetics, are unsuitable for drugs requiring a pulsatile release pattern that aligns with the physiological rhythm. Despite the therapeutic potential of marine-derived lovastatin in combination with colesevelam, no Pulsincap drug delivery system has yet been developed that combines lovastatin from mangrove-associated marine fungi and colesevelam to enable targeted release in the intestine and liver, taking spatial and temporal aspects into account.

[0005] Therefore, there is a need for a system capable of producing a Pulsincap dosage form that achieves improved LDL cholesterol reduction through combination therapy, while simultaneously enabling site-specific drug delivery based on the circadian rhythm and avoiding undesirable side effects associated with conventional formulations. SUMMARY OF THE INVENTION

[0006] The present invention relates to a system for producing a Pulsincap dosage form containing lovastatin, isolated from mangrove-associated marine fungi, and colesevelam for the treatment of hypercholesterolemia. The system comprises a fungal cultivation unit for obtaining lovastatin metabolite from marine fungi, a microsphere production unit for producing floating lovastatin microspheres by ionotropic gelation, a granulation unit for producing colesevelam granules, a capsule coating unit for applying a cellulose acetate phthalate coating, and a plug production unit for producing ethylcellulose-coated hydrogel plugs. The system enables spatially and temporally controlled drug release based on the circadian rhythm and delivers the active ingredients specifically to the sites of action in the intestine and liver.

[0007] The present disclosure relates to a system for the manufacture of a Pulsincap dosage form containing lovastatin and colesevelam for the treatment of hypercholesterolemia. The system comprises: a fungal cultivation unit for the cultivation of mangrove-associated marine fungi selected from the group consisting of Aspergillus sp., Penicillium sp., Rhizophus sp., and Fusarium sp., in production media for the manufacture of lovastatin metabolite; a microsphere manufacturing unit for the production of floating lovastatin microspheres by ionotropic gelation using chitosan, sodium alginate and calcium carbonate; a granulation unit for the production of colesevelam granules using explosives selected from the group consisting of croscarmellose and microcrystalline cellulose; a capsule coating unit for coating the capsule body with cellulose acetate phthalate (CAP); and a stopper manufacturing unit for the manufacture and coating of a hydrogel stopper with ethylcellulose.

[0008] One objective of the present disclosure is to provide a system for the manufacture of a Pulsincap dosage form containing lovastatin and colesevelam for the treatment of hypercholesterolemia.

[0009] Another objective of the present disclosure is to provide a system for manufacturing a Pulsincap dosage form that enables combination therapy of marine lovastatin and colesevelam to enhance the reduction of LDL cholesterol by 34% through a dual mechanism of action.

[0010] Another objective of the present disclosure is to enable spatial and temporal drug administration based on the circadian rhythm, whereby the drugs are delivered to the correct site of action in the intestine and liver, while simultaneously avoiding undesirable side effects.

[0011] Another objective of the present disclosure is the isolation of lovastatin from mangrove-associated marine fungi and its formulation into floating microspheres in combination with colesevelam granules in a pulsating release form.

[0012] However, another objective of the present disclosure is the reduction of LDL cholesterol by 34% (60 mg / dl) in a combination therapy based on the inhibition of cholesterol synthesis in the liver by lovastatin and in the intestine by colesevelam.

[0013] To further clarify the advantages and features of the present disclosure, the invention is described in more detail with reference to specific embodiments illustrated in the accompanying drawing. It is understood that this drawing merely shows typical embodiments of the invention and is therefore not to be understood as limiting its scope of protection. The invention is described and explained in more detail and with reference to the accompanying drawing. BRIEF DESCRIPTION OF THE IMAGE

[0014] These and other features, aspects and advantages of the present disclosure will be better understood when the following detailed description is read with reference to the accompanying drawing, in which the same symbols represent the same parts, wherein: Fig. Figure 1 shows a block diagram of a system for manufacturing a Pulsincap dosage form containing lovastatin and colesevelam for the treatment of hypercholesterolemia, according to an embodiment of the present disclosure.

[0015] Furthermore, those skilled in the art will recognize that the elements in the drawing are simplified and not necessarily drawn to scale. For example, the flowcharts illustrate the process by highlighting the main steps to facilitate understanding of the present disclosure. With regard to the construction of the device, one or more components may be represented in the drawing by conventional symbols. The drawing may show only those specific details relevant to understanding the embodiments of the present disclosure, so as not to clutter the drawing with details that are already apparent to those skilled in the art from the description contained herein. DETAILED DESCRIPTION:

[0016] To facilitate understanding of the principles of the invention, reference is made below to the embodiment shown in the drawing, which is described using specific terms. It is understood, however, that this does not limit the scope of protection of the invention. Rather, modifications and further developments of the depicted system, as well as further applications of the inventive principles shown therein, are conceivable, insofar as they would normally occur to a person skilled in the art in the field of the invention.

[0017] It will be clear to those skilled in the art that the foregoing general description and the following detailed description are exemplary and explanatory of the invention and are not to be understood as a limitation of it.

[0018] References to “an aspect”, “another aspect”, or similar phrases in this description mean that a particular feature, structure, or property described in connection with the embodiment is included in at least one embodiment of the present disclosure. Therefore, phrases such as “in one embodiment”, “in another embodiment”, and similar expressions in this description may, but do not necessarily, all refer to the same embodiment.

[0019] The terms "includes," "comprehensive," or similar expressions denote non-exclusive inclusion. Thus, a procedure or method containing a list of steps does not only include those steps but may also include further steps not explicitly listed or inherent in the procedure or method. Likewise, the statement "includes..." for one or more devices, subsystems, elements, structures, or components, without further limitations, does not preclude the existence of other devices, subsystems, elements, structures, or components.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meanings generally known to those skilled in the art in the field to which this invention belongs. The systems, methods, and examples described herein serve only for illustration and are not to be understood as limiting.

[0021] Embodiments of the present disclosure are described in detail below with reference to the attached drawing.

[0022] Fig. Figure 1 shows a block diagram of a system for manufacturing a Pulsincap dosage form containing lovastatin and colesevelam for the treatment of hypercholesterolemia, according to an embodiment of the present disclosure.

[0023] According to Fig.1 The system (100) comprises: a fungal cultivation unit (102) for cultivating mangrove-associated marine fungi, selected from the group consisting of Aspergillus sp., Penicillium sp., Rhizophus sp. and Fusarium sp., in production media for the manufacture of the lovastatin metabolite; a microsphere manufacturing unit (104) for the manufacture of floating lovastatin microspheres by ionotropic gelation using chitosan, sodium alginate and calcium carbonate; a granulation unit (106) for the manufacture of colesevelam granules using disintegrants selected from the group consisting of croscarmellose and microcrystalline cellulose; a capsule coating unit (108) for coating the capsule body with cellulose acetate phthalate (CAP); and a plug manufacturing unit (110) for the manufacture and coating of the hydrogel plug with ethylcellulose.

[0024] In one embodiment, the mushroom cultivation unit (102) is configured to use production media selected from the group consisting of maize, soybeans and coconut oilcake.

[0025] In one embodiment, the microsphere manufacturing unit (104) is configured to produce floating microspheres using a chitosan concentration in the range of 0.5% to 1.5%.

[0026] In one embodiment, the capsule coating unit (108) is configured to apply CAP coating in concentrations of 5% to 10%.

[0027] In one embodiment, the stopper preparation unit (110) is configured to apply an ethylcellulose coating in concentrations of 2.5% to 7.5%.

[0028] In one embodiment, the system (100) further comprises a characterization unit (112) configured to perform UV spectroscopy, FTIR analysis and TLC studies to confirm the lovastatin metabolite.

[0029] In one embodiment, the system (100) further comprises an evaluation unit (114) configured to assess the drug loading capacity, particle size analysis and bile salt binding ratio of the formulation.

[0030] In one embodiment, the system (100) further comprises a stability testing unit (116) configured to evaluate the stability of the formulation at 40°C±2°C and 75%±5% relative humidity.

[0031] The present invention relates to a system for producing a Pulsincap dosage form that combines marine lovastatin with colesevelam in a single formulation. The system enables the isolation and cultivation of lovastatin from mangrove-associated marine fungi, including Aspergillus sp., and achieves a superior LDL cholesterol reduction of 34% compared to monotherapy. The formulation allows for pulsatile drug release, synchronized with the circadian rhythm, thus ensuring targeted delivery to the intestine and liver. The system produces floating microspheres with optimized drug loading and colesevelam granules with excellent bile acid binding. These are encapsulated in CAP-coated capsules with ethylcellulose-coated hydrogel inserts for controlled release, thereby achieving improved therapeutic efficacy while minimizing side effects.

[0032] In one application, the prepared dose, consisting of marine lovastatin and colesevelam, is designed to lower LDL cholesterol by 34% (60 mg / dL) through a dual mechanism of action. Lovastatin inhibits cholesterol synthesis in the liver, while colesevelam does so in the intestine. When administered individually, lovastatin lowers LDL cholesterol by 22% (39 mg / dL) and colesevelam by 7% (13 mg / dL). The prepared dose is designed to be released at the site of action (intestine and liver) in accordance with the body's circadian rhythm. This ensures precise drug release in terms of both time and location, thus avoiding undesirable side effects. The primary reason for using pulsatile release is that constant drug release (zero-order kinetics) is not desirable.

[0033] In one embodiment, the system comprises a fungal cultivation unit configured for the isolation of fungi of the genus Aspergillus. The cultivation unit is used for the propagation and harvesting of fungi in production media according to standard procedures. It utilizes three different production media: corn, soybean, and coconut oilcake. Compared to soybean and coconut oilcake media, the system exhibited superior growth using corn production medium. The unit also includes a characterization unit that subjects the metabolites isolated from the various production media to UV, FTIR, and TLC analyses for confirmation. The characterization unit is configured such that the metabolites from corn closely resemble the standard drug lovastatin. It detects the absorption maximum of the metabolite at 264 nm, which corresponds to the absorption maximum of lovastatin.Using an FT-IR spectrometer, strong and characteristic peaks are obtained, confirming the presence of functional groups in the metabolite. The unit also generates a calibration curve by plotting extracts of known metabolite concentrations against the absorbance at 264 nm. The resulting standard curve is then linearly regressed.

[0034] In one embodiment, the system comprises a microsphere manufacturing unit for producing floating lovastatin microspheres via ionotropic gelation. The microsphere manufacturing unit is configured to formulate floating microspheres (LM1, LM2, LM3, LM4, LM5, LM6, LM7, LM8, and LM9) loaded with lovastatin metabolites using different chitosan concentrations (0.5%, 1.0%, 1.5%). The microsphere manufacturing unit is configured to use different amounts of the gelling polymer and the polymers (CaCO3 and sodium alginate) responsible for microsphere buoyancy in all formulations, while maintaining a constant drug quantity across all batches. The microsphere manufacturing unit is further configured to determine the drug loading capacity of the floating microspheres, with the ratio of the gelling polymer playing a key role.The system is configured to achieve maximum drug loading with 0.5% chitosan in combination with the active ingredient. The microsphere manufacturing unit is configured such that the calcium carbonate (CaCO3) ratio plays a key role in the formulation of floating microspheres. The microsphere manufacturing unit is also configured to optimize formulations LM4, LM5, and LM6 with respect to their drug loading efficiency. Of these three formulations, formulation LM5 showed a drug release of 78.86 ± 0.13% in the 12-hour in vitro release test.

[0035] In one embodiment, the system comprises a particle analysis unit with scanning electron microscopy (SEM) for analyzing microspheres of formulation LM5 loaded with lovastatin metabolites. The particle analysis unit is configured to show that formulation LM5, compared to two other batches, exhibits spherical, discrete particles with a size of 50 to 100 µm.

[0036] In one embodiment, the system includes a compatibility assessment unit configured to perform compatibility studies using FT-IR spectroscopy. The compatibility assessment unit compares the peak of the active ingredient with the peak of the drug-loaded, floating microspheres. The system demonstrates that the formulation peak remains unchanged, thus confirming the compatibility between the active ingredient and the polymer.

[0037] In one embodiment, the system comprises a granulation unit for producing colesevelam granules (C-F1 and C-F2) using two different explosives, croscarmellose and microcrystalline cellulose, according to the described process. The granulation unit is configured to perform physicochemical characterizations of the colesevelam granules, including angle of repose, bulk density, tapped density, Carr index, and Hausner ratio. Formulation C-F1 exhibits a Carr index of 1.69% and a Hausner ratio of 1.08, demonstrating excellent flow and compressibility properties. Compared to formulation C-F2, C-F1 achieves good results. The compatibility evaluation unit is further configured to perform a compatibility study of the colesevelam granules using FT-IR spectroscopy, which revealed no change in the functional groups.

[0038] In one embodiment, a binding study is performed to determine the binding ratio of the drug with bile salts. The maximum binding ratio of 1:3 is achieved after a 24-hour binding study with formulation C-F1.

[0039] In one embodiment, the system comprises a capsule coating unit that coats the capsule body with different CAP concentrations (5%, 7.5%, and 10%). The coating unit is configured such that the capsule body coated with 10% CAP is optimized due to the weight increase. The system further comprises a hydrogel plug manufacturing unit that coats the plugs with different ethylcellulose concentrations (2.5%, 5%, and 7.5%). The plug manufacturing unit is configured such that the hydrogel plug coated with 7.5% ethylcellulose is optimized because it exhibits a weight increase of over 2% compared to the others.

[0040] In one embodiment, the system is configured to invite the floating microspheres of the lovastatin-loaded formulation LM5 and the colesevelam granules (C-F1) into the gelatin capsule body coated with 10% cellulose acetate phthalate (CAP).

[0041] In one implementation, the optimized Pulsincap formulation exhibited a drug release of 82.42 ± 0.14% and a drug-to-bile salt binding ratio of 1:3.26, with the system following a non-Ficks release pattern. The manufactured dosage was tested for three months in a stability test facility according to standard procedures. The facility was configured to ensure that the formulation showed no significant changes in appearance, drug loading, or binding capacity during this period. The results demonstrated that the formulation was stable at 40 ± 2 °C and 75 ± 5% relative humidity.

[0042] The results showed that the system-prepared dosage, combined with marine organisms and the combination therapy of statins with bile acid sequestrants, lowers LDL cholesterol compared to conventional preparations.

[0043] The drawing and the preceding description illustrate embodiments. Those skilled in the art will recognize that one or more of the described elements can be combined to form a single functional element. Alternatively, certain elements can be divided into several functional elements. Elements of one embodiment can be added to another. For example, the process flows described here can be modified and are not limited to the manner described herein. Furthermore, the actions of a flowchart need not be performed in the sequence shown; nor do all actions necessarily need to be carried out. Actions that do not depend on other actions can be performed in parallel with the other actions. The scope of protection of the embodiments is in no way limited by these specific examples. Numerous variations, whether explicitly stated in the description or not, such as...Differences in structure, dimensions, and materials are possible. The scope of protection of the embodiments is at least as comprehensive as described by the following claims.

[0044] The advantages, other benefits, and problem solutions have been described above with reference to specific embodiments. However, the advantages, benefits, problem solutions, and any components that can effect or enhance an advantage, benefit, or solution are not to be construed as critical, necessary, or essential features or components of the claims. REFERENCES 100 A system for the manufacture of a Pulsincap dosage form containing lovastatin and colesevelam for the treatment of hypercholesterolemia. 102 Mushroom cultivation units 104 Microsphere Preparation Unit 106 granulation units 108 capsule coating unit 110 Plug preparation unit 112 Characterization Unit 114 Evaluation Unit 116 Stability tester

Claims

[1] A system for manufacturing a Pulsincap dosage form containing lovastatin and colesevelam for the treatment of hypercholesterolemia, comprising: a) a fungal cultivation facility configured to cultivate mangrove-associated marine fungi from the group consisting of Aspergillus sp., Penicillium sp., Rhizophus sp. and Fusarium sp. in production media to produce the metabolite lovastatin; b) a microsphere preparation plant for the production of floating lovastatin microspheres using ionotropic gelation technology with chitosan, sodium alginate and calcium carbonate; c) a granulation plant for the production of colesevelam granules using explosives from the group consisting of croscarmellose and microcrystalline cellulose; d) a capsule coating unit configured to coat the capsule body with cellulose acetate phthalate (CAP); and e) a stopper preparation unit configured to prepare hydrogel stoppers and coat them with ethylcellulose. [2] System according to claim 1, wherein the mushroom cultivation unit is configured to use production media selected from the group consisting of maize, soybeans and coconut oilcake. [3] System according to claim 1, wherein the microsphere manufacturing unit is configured to produce floating microspheres using a chitosan concentration in the range of 0.5% to 1.5%. [4] System according to claim 1, wherein the capsule coating unit is configured to apply CAP coating in concentrations of 5% to 10%. [5] System according to claim 1, wherein the stopper preparation unit is configured to apply an ethylcellulose coating in concentrations of 2.5% to 7.5%. [6] System according to claim 1, further comprising a characterization unit configured to perform UV spectroscopy, FTIR analysis and TLC studies to confirm the lovastatin metabolite. [7] System according to claim 1, further comprising an evaluation unit for assessing the drug loading capacity, particle size analysis and bile salt binding ratio of the formulation. [8] System according to claim 1, further comprising a stability test unit for evaluating the stability of the formulation at 40°C±2°C and 75%±5% relative humidity.

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