Arunai College Of Pharmacy, Tiruvannamalai, Tamil Nadu.
Gaucher disease is a rare lysosomal storage disorder caused by a deficiency in the enzyme glucocerebrosidase, leading to the accumulation of glucocerebroside in organs such as the spleen, liver, and bone marrow. Current treatment strategies include enzyme replacement therapy (ERT) and substrate reduction therapy (SRT), with Miglustat being a key oral therapeutic agent. This study focuses on developing a sustained-release matrix tablet formulation of Miglustat to enhance its therapeutic efficacy and patient compliance.The formulation was prepared using the direct compression method, incorporating Hydroxypropyl Methylcellulose (HPMC) as a release-retardant polymer, along with other excipients like magnesium stearate and polyvinylpyrrolidone. The prepared tablets were evaluated for micromeritic properties, weight variation, hardness, friability, thickness, drug content uniformity, and in vitro drug release. Stability studies were conducted as per ICH guidelines under different temperature and humidity conditions.Results showed that the formulated sustained-release Miglustat tablets exhibited desirable physical and mechanical properties, ensuring controlled drug release. The optimized formulation met pharmacopoeial standards, demonstrating its potential for improved therapeutic management of Gaucher’s disease.
Gaucher disease is a rare, inherited metabolic disorder in which deficiency of the enzyme glucocerebrosidase results in the accumulation of harmful quantities of certain fats (lipids), specifically the glycolipid glucocerebroside, through out the body especially within the bone marrow, spleen and liver. The main sources of glucoce rebro side in phagocytic cell sarethe membrane glycolipids of old leukocytes and erythrocytes, while the deposits in the neurons consist of gangliosides. Gaucher disease represents a proto type of rare lysosomal diseases for development of diagnostic and management algorithms based on regional characteristics as well as transformative therapies, including Enzyme replacement therapy (ERT) and recently approved, oral Substrate reduction therapy (SRT). In case of diagnostic delay, patients suffer from disabling and potentially life threatening complications. Hence, it is important to diagnose and manage Gaucher disease in a timely and optima lmanner.We here in provide guidelines and recommendations for an optimal approach to diagnosis and management of Gaucher disease in Indian patients.
History:
It was first described by Dr.Philippe Charles Ernest Gaucher in 1882.He was puzzled by a patient who had an enlarged spleen. He thought the patient died of leukemia. However, during the autopsy, he discovered that the spleen wasn’t just engorged, the organ It self had enlarged cells. Those enlarged cells are now known as Gaucher cells, and the enlarged spleen is a hallmark of the disease. In the early 1900s, Dr. Nathan Brill, an American pathologist suggested that Gaucher disease is an inherited condition and that both parents had to pass on the gene for their child to develop GD. Dr. Brill was also the first to use the name “Gaucher’s disease” and the first to diagnose a living patient. In 1934, a French chemist discovered what causes the spleens and livers to enlarge: A lipid (fatty substance) called glucocerebroside builds up in the organs. This buildup causes the symptoms of GD, such as the spleen and liver enlargement, anemia, fatigue, and bone problems. In the 1960s, Dr. Roscoe Brady, an American biochemist, was working with a team and explored why people with GD produce too much glucocerebroside. Dr. Brady’s team realized that patients with GD lack the enzyme glucocerebrosidase, which breaks down glucocerebroside. Their bodies produce a normal amount of glucocerebroside, but the enzyme doesn’t break it down, so it accumulates. They also discovered that the enzyme was not entirely lacking in patients with GD. It was slightly active—at 10-20?tivity. And the highest level of activity was in the lysosomes, inside the cell, so GD became known as a lysossomal storage disease.
Disease Profile:
Gaucher disease is categorized as a lysosomal storage disorder (LSD). Lysosomes are the major digestive units in cells. Enzymes within lysosomes break down or “digest” nutrients, including certain complex carbohydrates and fats. In Gaucher disease certain sugar (glucose) containing fat, known as glycolipids, abnormally accumulate in the body because ofthe lack of the enzyme, glucocerebrosidase. This accumulation or “storage” of lipids leads to the various symptoms or physical findings associated with a lysosomal storage disease. Gaucher disease is the second most common type of lysosomal storage disorder. (Recent publications indicate that Fabry disease is the most prevalent LSD).
Causes:
?Gaucher disease is caused by changes(mutations)in the GBA gene.
?All three forms of Gaucher disease are inherited in an autosomal recessive pattern. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.
?Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives form each parent one normal gene and One up abnormal gene for disease ,the person will be a carrier for the disease, but usually will not show symptoms.
?The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Pathophysiology:
Hydrolysis of glucosylceramide (GlcCer) by glucocerebrosidase (GCase) in the lysosome. GCase is activated by saposinC. In lysosomal storage diseases, an enzyme deficiency is responsible for the accumulation of its substrate in the cell lysosome (overload disease). Gaucher disease is caused by a deficiency in glucocerebrosidase (G Case) (or ?- glucosidase).
Accumulation glucosylceramide forms fibrillar that accumulate in macrophages and result in the cell cytoplasm presenting a characteristic “crumpled tissue paper”.
Types:
Clinically, 3 subtypes of Gaucher’s disease are identified based on neuronopathic involvement:
Signs And Symptoms:
While Gaucher disease manifests with vast clinical heterogeneity, it traditionally has been differentiated into the following 3 clinical subtypes, delineated by the absence or presence of neurologic involvement and its progression :
?Type1-Non neuronopathic Gaucher disease
?Type2-Acute neuronopathic Gaucher disease
?Type3-Chronic neuronopathic Gaucher disease
•Patients with type 1disease commonly present with painless splenomegaly, anemia, or thrombocytopenia. They may have chronic fatigue, hepatomegaly (with or without abnormal liver function test findings), bone pain, or pathologic fractures and may bruiseeasilybecauseofthrombocytopenia.Bleedingsecondarytothrombocytopenia may manifest as nosebleeds, bruising, or both.
•Patients with type 2 disease may present prenatally, at birth or during infancy with increased tone, seizures, strabismus, and organomegaly. Failure to thrive, swallowing abnormalities, oculomotorapraxia, hepatosplenomegaly, and stridor due to laryngospasm are typical in infants with type 2 disease.
•Patients with type 3 disease, in addition to organomegaly and bony involvement, present with neurologic involvement, most of tenincluding slowing of the horizontal saccadic eye movements. The neurologic manifestations may be mild or present subtly in infancy to early childhood.
•More rarely, Gaucher disease affects the brain,which can cause abnormal eye movements, muscle rigidity, swallowing difficulties and seizures
Diagnosis:
A diagnosis of Gaucher disease should be considered in individuals with unexplained anemia and easy bruising, particularly if they have enlargement of the spleen and liver and fractures. The diagnosis of Gaucher disease may be confirmed by a thorough clinical evaluation and a variety of specialized tests, particularly tests (i.e., enzyme assay) that measure acid beta-glucosidase activity in white blood cells (leukocytes) or skin cells (fibroblasts) and genetic (DNA) analysis for the causal gene defects (mutations).Note: the enzyme test cannot reliably detect carriers. The enzyme assay test is known as BGL (beta-glucosidaseleukocyte) blood test. This is a standard tool used by physicians to diagnose someone who is thought to have Gaucher disease, because usually the sepatients have low glucocerebrosidase enzyme activity. If the results are slightly low, the individual would be then referred by the physician to undergo genetic testing for mutations in the GBA gene. Genetic testing is done via blood or saliva.
Identification of two causal gene defects, in conjunction with enzyme test results, confirms the diagnosis of Gaucher disease. Individuals in whom only as in gle gene defect is identified maybe a carrier or,in the presence of low beta-glucosidase, maybe affected with a second gene defect (mutation) not detected. Referral to an appropriate genetic specialist may be indicated in this situation. DNA analysis identifies individuals who carry a mutation in the GBA gene who can pass the mutation to children. Prenatal diagnosis of Gaucher disease is possible if a known GBA gene mutation is present inthefamily.Testing can be done through amnio cente sis orchorionicvillus sampling(CVS), but is uncommon unless there is a family history of Gaucher disease type 2. During amniocentesis, a sample of fluid that surrounds the fetus (amniotic fluid) is removed and analyzed, whereas CVS involves the removal of tissue samples from a portion of the placenta. Prenatal diagnosis can confirm a definite diagnosis of Gaucher disease but does not determine the type of disease.
Treatment:
?Enzyme replacement therapy, which is effective for types1and 3.
?Medicines.
?Regular physical exams and bone density screening to check your disease.
?Bone marrow transplant.
?Surgery to remove all or part of your spleen.
?Joint replacement surgery.
?Blood transfusion
Methods Of Preparation:
Direct Compression:
In this process powdered materials are compressed directly without changing the properties of the drug like physical and chemical properties. Formulation of sustained release matrix tablets of miglustat:
Miglitol tablets with sustained release were made by the direct compression method Hydroxypropylmethylcellulose (HPMC) was used as a retardant material for preparation of tablets. The use of other excipients were magnesium stearate as a lubricant and the polyvinylpyrrolidone use as binder. For preparation of Sustained release tablets of miglitol, drug and polymer were weighed accurately, all the ingredients were sieved through 40 mesh screen and mixed with other ingredients and the powder mixture was compressed using tablet compression machine . Tablet compression weight was adjusted to 500mg.In total,3 formulations containing different amounts of HPMC K4,EC were prepared.
Micromeritic properties:
The angle of repose was measured by using funnel method, which indicate the flow ability of the granules.Loose bulk density and tapped density was measured using the formula:LBD=weight of the powder/ volume of packing. TBD= weight of the powder / tapped volume of the packing.
Compressibility index of the granules was determined by using the formula:CI(%)=[(TBD-LBD/TBD] X 100.
Evaluation Of Powder:
Bulk Density And Tapped Density:
The bulk density and tapped density were calculated using the following formulas.
Bulk density = W/Vo
Tapped-density=W/Vf Where,
Vo=initial volume Vf = final volume.
Compressibility index:
The Compressibility index and Hausner ratio are measures of the propensity of a powder to be compressed. As such, they are measures of the relative importance of inter particle interactions. The compressibility index and Hausner ratio maybe calculated using measured values for bulk density( bulk) and tapped density ( tapped) as follows.
CI=100[(?T??B)/?B].
Angle of Repose:
The frictional forces in a loose powder can be measured by the angle of repose,?.
? = tan-1 (h/r)
Where,
h=height of the heap.
r=radius of the heap.
It is determined by pouring the powder aconical on a level, flat surface, measured the included angle with the horizontal.
Evaluation Of Tablets:
All prepared tablets were evaluated for its assay, weight variation, hardness, Friability thickness and diameter.
Thickness:
Thickness was measured using a calibrated screw gauge meter. Five tablets of the formulation were picked randomly and thickness was measured individually.
Hardness:
The hardness of the tablets was determined using Monsanto Hardness tester. It is expressed in kg/cm2. Six tablets were randomly picked from each formulation and the mean and standard deviation values were calculated.
Friability:
A friability test was conducted on the tablets using a Roche friabilator. Twenty tablets were selected from each batch and any loose dust was removed with the help of a soft brush. The tablets were initially weighed (W initial) and transferred into friabilator. The drum was rotated at 25 rpm for 4 Minutes after which the tablets were removed. Any loose dust was removed from the tablets as before and the tablets were weighed again (W final). The percentage friability was then calculated by,
%F={1-(Wt/W)}×100
Where,
%F=Friability in percentage
W = Initial weight of tablets
Wt=Weight of tablets after revolution.
Weight variation:
Twenty tablets were randomly selected from each batch and individually weighed. The average weight and standard deviation of 20tablets was calculated. The batch passes the test for weight variation. If not more than two of the individual tablet weight deviate from the average weight.
Assay test:
Few tablets were weighed and triturate from that transfer an accurately weighed partition of the powder equivalent about 100mg of Miglitol at100ml volumetric flask containing buffer solution and then concentration is measured at max 222nm.
Uniformity of Content:
Five randomly selected tablets were weighed and powdered. The powdered tablet equivalent to 100 mg drug in one tablet was taken and transferred in a 250ml flask containing 100ml of 0.1N HCl (pH 1.2),phosphate buffer pH3.4, pH4.6, pH6.0 & pH7.4.The flask was on a shaken on a flask shaker for 24 hours and was kept for 12 hours for the sedimentation of undissolved materials. The solution is filtered through Whatman filter paper (0.45µm). 10ml of this filtrate was taken and appropriate dilution was made. The samples were analyzed at 276nm using UV visible spectrophotometer. The drug content was determined from the standard curve prepared at ? max 222 nm.
Stability Studies:
Selected formulations were subjected to stability studies as per I.C.H. Guidelines. Following conditions were used for stability studies.
30C/65 % RH analyzed till a period of 30 days . 40C/75 % RH analyzed till a period of 30 days.
Hardness, Friability, drug content and invitro release
CONCLUSION:
The study highlights the importance of sustained-release Miglustat tablets in improving treatment efficacy for Gaucher’s disease. By using hydroxypropylmethylcellulose (HPMC) and other excipients, the formulation ensures controlled drug release, enhancing patient compliance and therapeutic outcomes. The evaluation of tablets, including tests for hardness, friability, weight variation, and drug content, confirms the effectiveness of the formulation. Stability studies further validate the reliability of the developed tablets. Overall, the research demonstrates that sustained-release Miglustat tablets can offer a promising approach to managing Gaucher’s disease efficiently.
REFERENCES
S. Nivetha*, S. K. Senthilkumar, R. Bharathi, S. Bhuvana, S. M. Deena, J. Hari Haran, Formulation And Evaluation of Miglustat Sustained Release Matrix Tablet in The Treatment of Gaucher’s Disease, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 2, 1076-1083. https://doi.org/10.5281/zenodo.14871268
10.5281/zenodo.14871268
